Heterocyclic compounds and their use as medicaments

ABSTRACT

The present invention relates to new heterocyclic derivatives having an inhibitory activity on calpains and/or a trapping activity on reactive oxygen species, of formula  
                 
 
     in which A, X, Y, R1, R 2  and Het represent variable groups.  
     The invention also relates to their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular as inhibitors of calpains and/or traps of reactive oxygen species, selectively or non-selectively.

[0001] The present invention relates to new heterocyclic derivativeshaving an inhibitory activity on calpains and/or a trapping activity onreactive oxygen species (ROS's). The invention also relates to methodsfor their preparation, pharmaceutical preparations containing them andtheir use for therapeutic purposes, in particular as inhibitors ofcalpains and selective or non-selective ROS traps.

[0002] Given the potential role of calpains and ROS's inphysiopathology, the new derivatives according to the invention canproduce beneficial or favourable effects in the treatment of pathologiesinvolving these enzymes and/or these radicular species, and inparticular:

[0003] inflammatory and immunological diseases such as for examplerheumatoid arthritis, pancreatitis, multiple sclerosis, inflammation ofthe gastro-intestinal tract (ulcerative or non-ulcerative colitis,Crohn's disease),

[0004] cardiovascular and cerebrovascular diseases including for examplearterial hypertension, septic shock, cardiac or cerebral infarctions ofischemic or hemorragic origin, ischemia as well as disorders linked toplatelet aggregation,

[0005] disorders of the central or peripheral nervous system such as forexample neurodegenerative diseases where there can in particular bementioned trauma to the brain or spinal cord, sub-arachnoidhaemorrhages, epilepsy, ageing, senile dementia, including Alzheimer'sdisease, Huntington's chorea, Parkinson's disease, peripheralneuropathies,

[0006] osteoporosis,

[0007] muscular dystrophies,

[0008] proliferative diseases such as for example atherosclerosis orrecurrence of stenosis,

[0009] cataracts,

[0010] organ transplants,

[0011] auto-immune and viral diseases such as for example lupus, AIDS,parasitic and viral infections, diabetes and its complications, multiplesclerosis,

[0012] cancer,

[0013] all the pathologies characterized by an excessive production ofROS's and/or activation of calpains.

[0014] In all these pathologies, there is experimental evidencedemonstrating the involvement of ROS's (Free Radic. Biol. Med. (1996)20, 675-705; Antioxid. Health. Dis. (1997) 4 (Handbook of SyntheticAntioxidants), 1-52) as well as the involvement of calpains (TrendsPharmacol. Sci. (1994) 15, 412419; Drug News Perspect (1999) 12, 73-82).For example, cerebral lesions associated with cerebral infarction orexperimental cranial trauma are reduced by antioxidants (Acta. Physiol.Scand. (1994) 152, 349-350; J. Cereb. Blood Flow Metabol. (1995) 15,948-952; J Pharmacol Exp Ther (1997) 2, 895-904) as well as byinhibitors of calpains (Proc Natl Acad Sci U S A (1996) 93, 3428-33;Stroke, (1998) 29, 152-158; Stroke (1994) 25, 2265-2270).

[0015] A subject of the present invention is therefore compounds ofgeneral formula (I)

[0016] in which

[0017] R¹ represents a hydrogen atom, an —OR³, —SR³, oxo or cyclicacetal radical,

[0018] in which R³ represents a hydrogen atom, an alkyl, arylalkyl,heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonylradical,

[0019] in which the alkyl, aryl or heterocycloalkyl radicals areoptionally substituted by one or more identical or differentsubstituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or—NR⁴R⁵;

[0020] R⁴ and R⁵ represent, independently, a hydrogen atom or an alkylradical, or R⁴ and R⁵ together with the nitrogen atom to which they areattached form an optionally substituted heterocycle,

[0021] R² represents a hydrogen atom, an alkyl, aryl or aralkyl radical,the aryl group being optionally substituted by one or more identical ordifferent radicals chosen from: —OR⁶, —NR⁷R⁸, halogen, cyano, nitro oralkyl,

[0022] in which R⁶, R⁷ and R⁸ represent, independently, a hydrogen atom,an alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonylradical;

[0023] A represents

[0024] either an A1 or A′1 radical

[0025] in which R⁹, R¹⁰, R¹¹, R¹², R¹³ represent, independently, ahydrogen atom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitroor —NR¹⁵R¹⁶ radical,

[0026] R¹⁵ and R¹⁶ represent, independently, a hydrogen atom, an alkylradical or a —COR¹⁷ group, or R¹⁵ and R¹⁶ together with the nitrogenatom to which they are attached form an optionally substitutedheterocycle,

[0027] R¹⁷ represents a hydrogen atom, an alkyl, alkoxy or —NR¹⁸R¹⁹radical,

[0028] R¹⁸ and R¹⁹ represent, independently, a hydrogen atom or an alkylradical, or R¹⁸ and R¹⁹ together with the nitrogen atom to which theyare attached form an optionally substituted heterocycle,

[0029] R¹⁴ represents a hydrogen atom, an alkyl radical or a —COR²⁰group,

[0030] R²⁰ represents a hydrogen atom, an alkyl, alkoxy, aryl, aralkyl,heterocycloalkyl or —NR²¹R²² radical,

[0031] in which the alkyl, aryl or heterocycloalkyl radicals areoptionally substituted by one or more identical or differentsubstituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or—NR⁴R⁵;

[0032] R²¹ and R²² represent, independently, a hydrogen atom or an alkylradical, or R²¹ and R²² together with the nitrogen atom to which theyare attached form an optionally substituted heterocycle,

[0033] W represents a bond, O or S or also an —NR²³ radical, in whichR²³ represents a hydrogen atom or an alkyl radical;

[0034] or an A2 radical

[0035] in which

[0036] R²⁴, R²⁵ and R²⁶ represent, independently, a hydrogen, a halogen,the OH or SR²⁷ group, an alkyl, alkenyl, alkoxy radical or an —NR²⁸R²⁹radical,

[0037] R²⁷ represents a hydrogen atom or an alkyl radical,

[0038] R²⁸ and R²⁹ represent, independently, a hydrogen atom, an alkylradical or a —COR³⁰ group, or R²⁸ and R²⁹ form together with thenitrogen atom to which they are attached an optionally substitutedheterocycle,

[0039] R³⁰ represents a hydrogen atom, an alkyl, alkoxy or —NR³¹R³²radical,

[0040] R³¹ and R³² represent, independently, a hydrogen atom or an alkylradical, or R³¹ and R³² together with the nitrogen atom to which theyare attached form an optionally substituted heterocycle,

[0041] Q represents —OR³³, —SR³³, —NR³⁴R³⁵ or an aryl radicalsubstituted by one or more identical or different substituents chosenfrom: halogen, the OH group, an alkyl, alkoxy, cyano, nitro or —NR¹⁵R¹⁶radical,

[0042] R³³ represents a hydrogen atom, an alkyl, arylalkyl,heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonylradical,

[0043] in which the alkyl, aryl or heterocycloalkyl radicals areoptionally substituted by one or more identical or differentsubstituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or—NR⁴R⁵;

[0044] R³⁴ and R³⁵ represent, independently, a hydrogen atom, an alkylradical or a —CO—R³⁶ radical, or together with the nitrogen atom towhich they are attached form an optionally substituted heterocycle,

[0045] R³⁶ representing an alkyl radical;

[0046] or an A3 radical

[0047] in which R³⁷ represents a hydrogen atom, an alkyl, arylalkyl,heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonylradical,

[0048] in which the alkyl, aryl or heterocycloalkyl radicals areoptionally substituted by one or more identical or differentsubstituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or—NR⁴R⁵;

[0049] T represents a —(CH₂)_(m)— radical with m=1 or 2;

[0050] or an A4 radical

[0051] in which R³⁸ represents a hydrogen atom, an alkyl,—(CH₂)_(q)—NR³⁹R⁴⁰ or aralkyl radical, the aryl group being optionallysubstituted by one or more identical or different substituents chosenfrom: OH, alkyl, halogen, nitro, alkoxy or —NR³⁹R⁴⁰,

[0052] q being an integer comprised between 2 and 6;

[0053] or an A5 radical

[0054] in which R′³⁸ and R″³⁸ represent independently a hydrogen atom,nitro, —NR′³⁹R′⁴⁰, an alkyl or arylalkyl radical, the aryl group beingoptionally substituted by one or more identical or differentsubstituents chosen from: OH, the alkyl, halogen, nitro, alkoxy or—NR³⁹R⁴⁰ radicals,

[0055] R′³⁹, R′⁴⁰, R³⁹ and R⁴⁰ represent, independently, a hydrogenatom, an alkyl radical or a —COR⁴¹ group, or R³⁹ and R⁴⁰ or R′³⁹ andR′⁴⁰ together with the nitrogen atom form an optionally substitutedheterocycle,

[0056] R⁴¹ represents a hydrogen atom, an alkyl, alkoxy or —NR⁴²R⁴³radical,

[0057] R⁴² and R⁴³ represent, independently, a hydrogen atom or an alkylradical, or R⁴² and R⁴³ together with the nitrogen atom to which theyare attached form an optionally substituted heterocycle,

[0058] T representing a —(CH₂)_(m)— radical with m=1 or 2,

[0059] or finally an A6 radical

[0060] in which R⁴⁴ represents a hydrogen atom, the OH group or an alkylor alkoxy radical;

[0061] X represents —(CH₂)_(n)—, —(CH₂)_(n)—CO—,—N(R⁴⁵)—CO—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—D—CO—, —CO—N(R⁴⁵)—CO—, —CO—D—CO—,—CH═CH—(CH₂)_(n)—CO—, —N(R⁴⁵)—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—C(R⁴⁶R⁴⁷)—CO—,—O—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—NH—C(R⁴⁶R⁴⁷)—CO—, —CO—N(R⁴⁵)—C(R⁴⁶R⁴⁷)—CO—,—S—(CH₂)_(n)—CO— or -Z-CO—;

[0062] D represents a phenylene radical optionally substituted by one ormore identical or different radicals chosen from alkyl, alkoxy, OH,nitro, halogen, cyano, or carboxyl optionally esterified by an alkylradical;

[0063] Z represents a heterocycle,

[0064] R⁴⁵ represents a hydrogen atom or an alkyl radical,

[0065] R⁴⁶ and R⁴⁷ represent, independently, a hydrogen atom, an alkyl,aryl or aralkyl radical the alkyl and aryl groups of which areoptionally substituted by one or more identical or differentsubstituents chosen from: the OH, —SH, halogen, nitro, alkyl, alkoxy,alkylthio, aralkoxy, aryl-alkylthio, —NR⁴⁸R⁴⁹ and carboxyl groupoptionally esterified by an alkyl radical;

[0066] R⁴⁸ and R⁴⁹ represent, independently, a hydrogen atom, an alkylradical or a —COR⁵⁰ group, or R⁴⁸ and R⁴⁹ together with the nitrogenatom to which they are attached form an optionally substitutedheterocycle,

[0067] R⁵⁰ represents a hydrogen atom, an alkyl, alkoxy or —NR⁵¹R⁵²radical,

[0068] R⁵¹ and R⁵² represent, independently, a hydrogen atom or an alkylradical, or R⁵¹ and R⁵² together with the nitrogen atom to which theyare attached, form an optionally substituted heterocycle;

[0069] n being an integer comprised between 0 and 6;

[0070] Y represents —(CH₂)_(p)—, —C(R⁵³R⁵⁴)—(CH₂)_(p)—, —C(R⁵³R⁵⁴)—CO—;

[0071] R⁵³ and R⁵⁴ represent, independently, a hydrogen atom, an alkylradical, an aralkyl radical the aryl group of which is optionallysubstituted by one or more identical or different substituents chosenfrom: the OH, halogen, nitro, alkyl, alkoxy, —NR⁵⁵R⁵⁶ group,

[0072] R⁵⁵ and R⁵⁶ represent, independently, a hydrogen atom, an alkylradical or a —COR⁵⁷ group, or R⁵⁵ and R⁵⁶ together with the nitrogenatom to which they are attached, form an optionally substitutedheterocycle,

[0073] R⁵⁷ represents a hydrogen atom, an alkyl, alkoxy or —NR⁵⁸R⁵⁹radical,

[0074] R⁵⁸ and R⁵⁹ represent, independently, a hydrogen atom or an alkylradical, or R⁵⁸ and R⁵⁹ together with the nitrogen atom to which theyare attached form an optionally substituted heterocycle;

[0075] p being an integer comprised between 0 and 6;

[0076] Het represents a heterocycle,

[0077] as well as the addition salts with mineral and organic acids orwith mineral and organic bases of said compounds of general formula (I),

[0078] with the exception of the compounds of formula (I) in which whenHet represents tetrahydrofuran or tetrahydropyran, R¹ represents the OR³radical with R³ representing a hydrogen atom, an alkyl, arylalkyl,heterocycloalkylcarbonyl radical the heterocycloalkyl radical of whichis connected by a carbon atom, alkylcarbonyl, arylcarbonyl oraralkylcarbonyl radical, R² represents a hydrogen and Y represents the—(CH₂)_(p)— radical with p=0, then X does not represent—CO—N(R⁴⁵)—C(R⁴⁶R⁴⁷)—CO— with R⁴⁵═R⁴⁶═H.

[0079] In certain cases, the compounds according to the presentinvention can comprise asymmetrical carbon atoms (of “R” or “S”configuration). As a result, the present invention includes theenantiomeric, diastereoisomeric forms and all combinations of theseforms, including the “RS” racemic mixtures. In an effort to simplifymatters, when no specific configuration is indicated in the structuralformulae, it should be understood that the two enantiomeric (ordiastereoisomeric) forms and their mixtures are represented.

[0080] By alkyl, unless specified otherwise, is meant a linear orbranched alkyl radical containing 1 to 6 carbon atoms such as, forexample, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexylradicals. The alkoxy radicals can correspond to the alkyl radicalsindicated above such as for example the methoxy, ethoxy, propyloxy orisopropyloxy radicals but also linear, secondary or tertiary butoxy.Similarly the alkylthio radicals can correspond to the alkyl radicalsindicated above such as for example methylthio or ethylthio.

[0081] By alkenyl, unless otherwise specified, is meant a linear orbranched alkyl radical containing 1 to 6 carbon atoms and having atleast one unsaturation (double bond). By halogen, is meant the fluorine,chlorine, bromine or iodine atoms.

[0082] By aryl, is meant a carbocyclic or heterocyclic system comprisingat least one aromatic ring, a system being called heterocyclic when atleast one of the rings composing it comprises a heteroatom (O, N or S).As an example of a carbocyclic aryl radical, there can be mentionedphenyl or naphthyl. As an example of a heterocyclic aryl radical (orheteroaryl), there can be mentioned thienyl, furyl, pyrrolyl,imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl,pyridyl, pyrazinyl, pyrimidyl, benzothienyl, benzofuryl and indolyl.

[0083] The term heterocycle (or heterocycloalkyl), represented forexample by the Het or Z radicals, preferably represents a saturated orunsaturated, mono or bicyclic heterocycle, comprising 1 to 5 heteroatomschosen from O, S, N. The nitrogen atom can optionally be substituted bya radical chosen from: alkyl, aryl, aralkyl and alkylcarbonyl. As anexample of a saturated heterocycle, there can be mentioned:tetrahydrofuran, tetrahydropyran, oxetane, oxepane, tetrahydrothiophene,tetrahydrothiopyran, thietane, pyrrolidine, piperidine, azetidine,1,3-dioxane, 1,3-dioxolane, 1,3-dithiolane, 1,3-dithiane,1,3-oxathiolane, 1,3-oxazolidine, 1,3-imidazolidine or 1,3-thiazolidine.As an example of an unsaturated heterocycle, there can be mentioned:thiophene, furan, pyrrol, imidazole, pyrazole, isothiazole, thiazole,isoxazole, oxazole, pyridine, pyrazine, pyrimidine, benzimidazole,benzofuran, benzopyran, 1,3-benzothiazole, benzoxazole, quinoline.

[0084] The arylalkyl (or aralkyl) radicals designate the radicals inwhich the aryl and alkyl radicals respectively are as defined above suchas for example benzyl, phenethyl or naphthylmethyl. The aralkoxy(aryl-alkoxy) radicals designate the radicals in which the aryl andalkoxy radicals respectively are as defined above such as for examplebenzyloxy or phenylethoxy. The arylalkylthio radicals designate theradicals in which the aryl and alkylthio radicals respectively are asdefined above such as for example benzylthio.

[0085] The alkylcarbonyl, heterocycloalkylcarbonyl, arylcarbonyl oraralkylcarbonyl radicals designate the radicals in which the alkyl,heterocycloalkyl, aryl and aralkyl radicals respectively have themeaning indicated previously.

[0086] In the case of radicals of formula —NR^(i)R^(j) where R^(i) andR^(j) together with the nitrogen atom to which they are attached form anoptionally substituted heterocycle, the heterocycle is preferablysaturated and comprises 4 to 7 members and 1 to 3 heteroatoms includingthe nitrogen atom already present, the additional heteroatoms beingchosen independently from the group constituted by the O, N and S atoms.Said heterocycle can be, for example, the azetidine, pyrrolidine,piperidine, piperazine, morpholine or thiomorpholine ring. Saidheterocycle can be substituted by one or more identical or differentsubstituents chosen from the hydroxy group, an alkyl, aryl, aralkyl oralkoxy radical or a halogen atom.

[0087] A more particular subject of the invention is the compounds offormula (I) as defined above, in which Het represents a monocyclicradical containing 1 to 2 heteroatoms chosen from O and N, andpreferably a radical corresponding to the tetrahydrofuran, dioxolane,pyrrolidine, 1,3-oxazolidine ring, and R¹ represents the hydrogen atom,the —OR³ or oxo radical.

[0088] A more particular subject of the invention is the compounds offormula (I) as defined above, in which X represents —(CH₂)_(n)—,—(CH₂)_(n)—CO—, —O—(CH₂)_(n)—CO—, —CO—N(R⁴⁵)—D—CO—,—N(R⁴⁵)—CO—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—C(R⁴⁶R⁴⁷)—CO—,—N(R⁴⁵)—CO—NH—C(R⁴⁶R⁴⁷)—CO—, —N(R⁴⁵)—(CH₂)_(n)—CO—,—CO—N(R⁴⁵)—C(R⁴⁶R⁴⁷)—CO— or —Z—CO—,

[0089] and preferentially when R⁴⁵ and R⁴⁷ represent the hydrogen atom,R⁴⁶ represents the hydrogen atom, an alkyl or phenyl radical, Drepresents the phenylene radical and Z represents the thiazole radical.

[0090] A more particular subject of the invention is also compounds offormula (I) as defined above, in which R² represents a hydrogen atom oran aralkyl radical, and preferably the benzyl radical.

[0091] A more particular subject of the invention is also compounds offormula (I) as defined above, in which A represents

[0092] either A1 with W representing the sulphur atom,

[0093] or A′1

[0094] or A2 with R²⁴, R²⁵ and R²⁶ which represent, independently, ahydrogen or an alkyl radical and Q which represents —OR³³,

[0095] or A3 with T representing the —(CH₂)₂— radical;

[0096] or A4 with T representing the —(CH₂)— radical,

[0097] and preferably the radicals of formula

[0098] A more particular subject of the invention is also the compoundsdescribed hereafter in the examples and preferably the productscorresponding to the following formulae:

[0099](2R)-6-hydroxy-N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;

[0100]N-1-(4-anilinophenyl)-N-4-[(3S)-2-hydroxytetrahydro-3-furanyl]succinamide;

[0101](3S)-3-{[4-(4-anilinoanilino)-4-oxobutanoyl]amino}tetrahydro-2-furanylacetate;

[0102]N-1-(4-anilinophenyl)-N-4-[(1S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl]succinamide;

[0103]N-1-(4-anilinophenyl)-N-3-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenylmalonamide;

[0104] 3-(4-anilinoanilino)tetrahydro-2-furanol;

[0105]N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;

[0106](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)-amino]pentanoyl}amino)tetrahydro-2-furanylacetate;

[0107]N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;

[0108]N-[4-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;

[0109]N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;

[0110](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylpivalate;

[0111](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl3,3-dimethylbutanoate;

[0112](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylbenzoate;

[0113](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylphenylacetate;

[0114](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl(2S)-2-(dimethylamino)-3-phenylpropanoate;

[0115](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl4-morpholinecarboxylate;

[0116]N-{(1S)-3-methyl-1-[(3-oxo-1-pyrrolidinyl)carbonyl]butyl}-10H-phenothiazine-2-carboxamide;

[0117]2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-hydroxytetrahydro-3-furanyl]acetamide;

[0118]N¹-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenyl-N³-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide;

[0119] N-(2-anilinophenyl)-N′-[(3S)-2-hydroxytetrahydro-3-furanyl]urea;

[0120]N¹-[(3S)-2-hydroxytetrahydro-3-furanyl]-N²-(1-propyl-2,3-dihydro-1H-indol-5-yl)ethanediamide;

[0121](2R)-N-[(1S)-1-(1,3-dioxolan-2-yl)-2-phenylethyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;

[0122] N-[(3S)-2-hydroxytetrahydro-3-furanyl]-5-indolinecarboxamide.

[0123] The compounds of formula I according to the invention can beprepared via several synthesis routes according to the definition of thevariable groups.

[0124] The compounds of general formula (I) in which Het represents thetetrahydrofuran ring and Y represents the —(CH₂)_(p) radical, can beprepared according to the following diagram:

[0125] in which A, X, R² and R³ are as described above,

[0126] by condensation of the acids of general formula (II) on theamines of general formula (III), under standard conditions for peptidesynthesis (M. Bodanszky and A. Bodanszky, The Practice of PeptideSynthesis. 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMFin the presence of a coupling reagent such as dicyclohexylcarbodiimide(DCC), 1,1′-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23),4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC or WSCI) (John Jones, The chemical synthesis ofpeptides, 54 (Clarendon Press, Oxford, 1991)) in order to produce theintermediate carboxamides of general formula (IV). The lactonic ring ofthe intermediates of general formula (IV) is then reduced using areducing agent such as, for example, diisobutylaluminium hydride(DIBAL), in an inert solvent such as, for example, THF or CH₂Cl₂, at atemperature varying from 0 to −78° C. The lactol derivative of generalformula (I′) obtained in this way can be acylated using, for example, anacid chloride (R³—Cl) or an acid anhydride (acetic anhydride, benzoylchloride, etc.) in the presence of a base such as, for example,triethylamine, in an inert solvent such as for example CH₂Cl₂ in orderto produce the compound of general formula (I).

[0127] The compounds of formula (I) in which Het represents thepyrrolidinyl radical and Y represents —C(R⁵³R⁵⁴)—CO—, R⁵³ and R⁵⁴ beingas defined above, can be prepared according to the following diagram:

[0128] in which A, X and R² are as described above,

[0129] by condensation of the acids of general formula (V) on the aminesof general formula (VI) (J. Med. Chem. (1992) 35 (8), 1392-1398) understandard conditions for peptide synthesis, as described previously, inorder to produce the compounds of general formula (I′). The optionaldeprotection of the ketone function is then carried out according to themethods described in the literature (T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, Second edition(Wiley-Interscience, 1991)), in order to produce the compounds ofgeneral formula (I).

[0130] The compounds of formula (I) in Which Het represents the1,3-dioxolane, 1,3-dioxane, 1,3-dithiane, 1,3-dithiolane,1,3-oxathiolane, 1,3-oxazolidine, 1,3-imidazolidine or 1,3-thiazolidinering, and Y represents —C(R⁵³R⁵⁴)—CO—, R⁵³ and R⁵⁴ being as definedabove, can be prepared according to the following diagram:

[0131] in which A, X and R² are as described above and V and V′represent independently N, O or S,

[0132] by condensation of the acids of general formula (II) describedpreviously, on the commercial amino-esters of general formula (VII),under the standard conditions for peptide synthesis describedpreviously, in order to produce the intermediates of general formula(VIII). Reduction of the carboxylic ester using a reducing agent suchas, for example, DIBAL, in an inert solvent such as, for example, THF orCH₂Cl₂, at a temperature varying from 0 to −78° C., leads to thealdehydes of general formula (IX). Conversion of the aldehyde to aheterocycle is carried out according to the methods in the literature(T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,Second edition (Wiley-Interscience, 1991)).

[0133] The compounds of formula (I) in which Het represents theoxazolidine ring can be prepared according to the following diagram:

[0134] in which A, X, Y, R² and R³ are as described above,

[0135] by condensation of the acids of general formula (V) describedpreviously, with the commercial amino-esters of general formula (X)under the peptide synthesis conditions described previously. The estersof general formula (XI) obtained intermediately are then saponified inorder to produce carboxylic acids of general formula (XII), which byheating in the presence of paraformaldehyde and of an acid such as, forexample, PTSA, while continually trapping the water formed during thereaction using a device of Dean-Stark type, lead to the oxazolidinonesof general formula (XIII). These are then reduced using a reducing agentsuch as, for example, DIBAL, in an inert solvent such as, for example,THF or CH₂Cl₂, at a temperature varying from 0 to −78° C. in order toproduce oxazolidine derivatives of general formula (I′). The compoundsof general formula (I′) obtained in this way can be acylated using, forexample, an acid chloride (R³—Cl) or an acid anhydride (aceticanhydride, benzoyl chloride, etc.) in the presence of a base such as,for example, triethylamine, in an inert solvent such as for exampleCH₂Cl₂ in order to produce the compounds of formula (I).

[0136] The compounds of general formula (I) in which Het represents thetetrahydrofuran ring, X represents the —(CH₂)_(n)— radical (n=0) and Yrepresents the —(CH₂)_(p)— radical (p=0), can also be prepared accordingto the following diagram:

[0137] in which A, R² and R³ are as described above,

[0138] by nucleophilic substitution of the halogen of the lactones ofgeneral formula (XV) using the amines of general formula (II.1), whileheating the reaction mixture to a temperature varying from 50 to 110° C.in an inert solvent such as for example, acetonitrile or DMF, for aduration varying from 30 minutes to 5 hours, in order to produce theintermediates of general formula (XV). Reduction of the lactone functionfollowed by acylation of the lactol of general formula (I′) are carriedout under the conditions described previously.

[0139] The compounds of general formula (I) in which Het represents thetetrahydrofuran ring, X represents the —N(R⁴⁵)—(CH₂)_(n)—CO— radical(n=0) and Y represents the —(CH₂)_(p)— radical (p=0) are ureas which canbe prepared according to the following synthesis diagram:

[0140] in which A, R² and R³ are as described above,

[0141] by condensation of the amines of general formula (II.1) with theamines of general formula (III) in the presence of triphosgene and of abase such as, for example, diisopropylethylamine in an inert solventsuch as dichloromethane according to an experimental protocol describedin J. Org. Chem. (1994) 59 (7), 1937-1938. The lactonic ring of theureas of general formula (XVI) is then reduced and modified under theexperimental conditions described previously in order to produce thecompounds of general formula (I).

[0142] The compounds of the present invention have usefulpharmacological properties: they have an inhibitory activity on calpainsand/or a trapping activity on reactive oxygen species.

[0143] The compounds of the present invention can thus be used fordifferent therapeutic applications. They can produce beneficial orfavourable effects in the treatment of pathologies where these enzymesand/or these radicular species occur.

[0144] These properties render the products of formula I suitable forpharmaceutical use. A subject of the present Application is also, asmedicaments, the products of formula I as defined above, as well as theaddition salts with pharmaceutically acceptable mineral or organic acidsor mineral or organic bases of said products of formula I, as well asthe pharmaceutical compositions containing, as active ingredient, atleast one of the medicaments as defined above.

[0145] The invention therefore relates to pharmaceutical compositionscontaining a compound of the invention or a pharmaceutically acceptableaddition salt of the latter, in combination with a pharmaceuticallyacceptable support. The pharmaceutical composition can be in the form ofa solid, for example, powders, granules, tablets, gelatin capsules orsuppositories. The appropriate solid supports can be, for example,calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin,starch, gelatin, cellulose, methyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine and wax.

[0146] The pharmaceutical compositions containing a compound of theinvention can also be presented in liquid form, for example, solutions,emulsions, suspensions or syrups. Appropriate liquid supports can be,for example, water, organic solvents such as glycerol or glycols, aswell as their mixtures, in varying proportions, in water, added topharmaceutically acceptable oils or greases. Sterile liquid compositionscan be used for intramuscular, intraperitoneal or sub-cutaneousinjections and sterile compositions can also be administeredintravenously.

[0147] Certain compounds of general formula I described previously arecovered by the Application EP 641800. The compounds of this Applicationhave an inhibitory activity on cathepsine L which is different from theinhibitory activity on calpains and/or the trapping activity on reactiveoxygen species.

[0148] A subject of the invention is therefore also the use of compoundsof formula (I_(a)) as defined above,

[0149] in racemic, enantiomeric, diastereoisomeric form or allcombinations of these forms, in which

[0150] R_(a) ¹ represents a hydrogen atom, an —OR³, —SR³, oxo or cyclicacetal radical,

[0151] in which R³ represents a hydrogen atom, an alkyl, arylalkyl,heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonylradical,

[0152] in which the alkyl, aryl or heterocycloalkyl radicals areoptionally substituted by one or more identical or differentsubstituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or—NR⁴R⁵;

[0153] R⁴ and R⁵ represent, independently, a hydrogen atom or an alkylradical, or R⁴ and R⁵ together with the nitrogen atom to which they areattached form an optionally substituted heterocycle,

[0154] R_(a) ² represents a hydrogen atom, an alkyl, aryl or aralkylradical, the aryl group being optionally substituted by one or moreidentical or different radicals chosen from: —OR⁶, —NR⁷R⁸, halogen,cyano, nitro or alkyl,

[0155] in which R⁶, R⁷ and R⁸ represent, independently, a hydrogen atom,an alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonylradical;

[0156] A_(a) represents

[0157] either an Al1 or A′1 radical

[0158] in which R⁹, R¹⁰, R¹¹, R¹², R¹³ represent, independently, ahydrogen atom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitroor —NR¹⁵R¹⁶ radical,

[0159] R¹⁵ and R¹⁶ represent, independently, a hydrogen atom, an alkylradical or a —COR¹⁷ group, or R¹⁵ and R¹⁶ together with the nitrogenatom to which they are attached form an optionally substitutedheterocycle,

[0160] R¹⁷ represents a hydrogen atom, an alkyl, alkoxy or —NR¹⁸R¹⁹radical,

[0161] R¹⁸ and R¹⁹ represent, independently, a hydrogen atom or an alkylradical, or R¹⁸ and R¹⁹ together with the nitrogen atom to which theyare attached form an optionally substituted heterocycle,

[0162] R¹⁴ represents a hydrogen atom, an alkyl radical or a —COR²⁰group,

[0163] R²⁰ represents a hydrogen atom, an alkyl, alkoxy, aryl, aralkyl,heterocycloalkyl or

[0164] —NR²¹R²² radical,

[0165] in which the alkyl, aryl or heterocycloalkyl radicals areoptionally substituted by one or more identical or differentsubstituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or—NR⁴R⁵;

[0166] R²¹ and R²² represent, independently, a hydrogen atom or an alkylradical, or R²¹ and R²² together with the nitrogen atom to which theyare attached form an optionally substituted heterocycle,

[0167] W represents a bond, O or S or also an —NR²³ radical, in whichR²³ represents a hydrogen atom or an alkyl radical;

[0168] or an A2 radical

[0169] in which

[0170] R²⁴, R²⁵ and R²⁶ represent, independently, a hydrogen, a halogen,the OH or SR²⁷ group, an alkyl, alkenyl, alkoxy radical or an —NR²⁸R²⁹radical,

[0171] R²⁷ represents a hydrogen atom or an alkyl radical,

[0172] R²⁸ and R²⁹ represent, independently, a hydrogen atom, an alkylradical or a —COR³⁰ group, or R²⁸ and R²⁹ together with the nitrogenatom to which they are attached form an optionally substitutedheterocycle,

[0173] R³⁰ represents a hydrogen atom, an alkyl, alkoxy or —NR³¹R³²radical,

[0174] R³¹ and R³² represent, independently, a hydrogen atom or an alkylradical, or R³¹ and R³² together with the nitrogen atom to which theyare attached form an optionally substituted heterocycle,

[0175] Q represents —OR³³, —SR³³, —NR³⁴R³⁵ or an aryl radicalsubstituted by one or more identical or different substituents chosenfrom: halogen, the OH group, an alkyl, alkoxy, cyano, nitro or —NR¹⁵R¹⁶radical,

[0176] R³³ represents a hydrogen atom, an alkyl, arylalkyl,heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonylradical,

[0177] in which the alkyl, aryl or heterocycloalkyl radicals areoptionally substituted by one or more identical or differentsubstituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or—NR⁴R⁵;

[0178] R³⁴ and R³⁵ represent, independently, a hydrogen atom, an alkylradical or a —CO—R³⁶ radical, or together with the nitrogen atom towhich they are attached form an optionally substituted heterocycle,

[0179] R³⁶ representing an alkyl radical;

[0180] or an A3 radical

[0181] in which R³⁷ represents a hydrogen atom, an alkyl, arylalkyl,heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonylradical,

[0182] in which the alkyl, aryl or heterocycloalkyl radicals areoptionally substituted by one or more identical or differentsubstituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or—NR⁴R⁵;

[0183] T represents a —(CH₂)m— radical with m=1 or 2;

[0184] or an A4 radical

[0185] in which R³⁸ represents a hydrogen atom, an alkyl,—(CH²)_(q)—NR³⁹R⁴⁰ or aralkyl radical, the aryl group being optionallysubstituted by one or more identical or different substituents chosenfrom: OH, alkyl, halogen, nitro, alkoxy or —NR³⁹R⁴⁰,

[0186] q being an integer comprised between 2 and 6;

[0187] or an A5 radical

[0188] in which R′³⁸ and R″³⁸ represent independently a hydrogen atom,nitro, —NR′³⁹R′⁴⁰, an alkyl or arylalkyl radical, the aryl group beingoptionally substituted by one or more identical or differentsubstituents chosen from: OH, the alkyl, halogen, nitro, alkoxy or—NR³⁹R⁴⁰ radicals,

[0189] R′³⁹, R′⁴⁰, R³⁹ and R⁴⁰ represent, independently, a hydrogenatom, an alkyl radical or a —COR⁴¹ group, or R³⁹ and R⁴⁰ or R′³⁹ andR′⁴⁰ together with the nitrogen atom form an optionally substitutedheterocycle,

[0190] R⁴¹ represents a hydrogen atom, an alkyl, alkoxy or —NR⁴²R⁴³radical,

[0191] R⁴² and R⁴³ represent, independently, a hydrogen atom or an alkylradical, or R⁴² and R⁴³ together with the nitrogen atom to which theyare attached form an optionally substituted heterocycle,

[0192] T representing a —(CH₂)_(m)— radical with m=1 or 2,

[0193] or finally an A6 radical

[0194] in which R⁴⁴ represents a hydrogen atom, the OH group or an alkylor alkoxy radical;

[0195] X_(a) represents —(CH₂)_(n)—, —(CH₂)_(n)—CO—,—N(R⁴⁵)—CO—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—D—CO—, —CO—N(R⁴⁵)—CO—, —CO—D—CO—,—CH═CH—(CH₂)_(n)—CO—, —N(R⁴⁵)—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—C(R⁴⁶R⁴⁷)—CO—,—O—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—NH—C(R⁴⁶R⁴⁷)—CO—, —CO—N(R⁴⁵)—C(R⁴⁶R⁴⁷)—CO—,—S—(CH₂)_(n)—CO— or —Z—CO—;

[0196] D represents a phenylene radical optionally substituted by one ormore identical or different radicals chosen from alkyl, alkoxy, OH,nitro, halogen, cyano, or carboxyl optionally esterified by an alkylradical;

[0197] Z represents a heterocycle,

[0198] R⁴⁵ represents a hydrogen atom or an alkyl radical,

[0199] R⁴⁶ and R⁴⁷ represent, independently, a hydrogen atom, an alkyl,aryl or aralkyl radical the alkyl and aryl groups of which areoptionally substituted by one or more identical or differentsubstituents chosen from: the OH, —SH, halogen, nitro, alkyl, alkoxy,alkylthio, aralkoxy, aryl-alkylthio, —NR⁴⁸R⁴⁹ and carboxyl groupoptionally esterified by an alkyl radical;

[0200] R⁴⁸ and R⁴⁹ represent, independently, a hydrogen atom, an alkylradical or a —COR⁵⁰ group, or R⁴⁸ and R⁴⁹ together with the nitrogenatom to which they are attached form an optionally substitutedheterocycle,

[0201] R⁵⁰ represents a hydrogen atom, an alkyl, alkoxy or —NR⁵¹R⁵²radical,

[0202] R⁵¹ and R⁵² represent, independently, a hydrogen atom or an alkylradical, or R⁵¹ and R⁵² together with the nitrogen atom to which theyare attached form an optionally substituted heterocycle;

[0203] n being an integer comprised between 0 and 6;

[0204] Y_(a) represents —(CH₂)_(p)—, —C(R⁵³R⁵⁴)—(CH₂)_(p)—,—C(R⁵³R⁵⁴)—CO—;

[0205] R⁵³ and R⁵⁴ represent, independently, a hydrogen atom, an alkylradical, an aralkyl radical the aryl group of which is optionallysubstituted by one or more identical or different substituents chosenfrom: the OH group, halogen, nitro, alkyl, alkoxy, —NR⁵⁵R⁵⁶,

[0206] R⁵⁵ and R⁵⁶ represent, independently, a hydrogen atom, an alkylradical or a —COR⁵⁷ group, or R⁵⁵ and R⁵⁶ together with the nitrogenatom to which they are attached form an optionally substitutedheterocycle,

[0207] R⁵⁷ represents a hydrogen atom, an alkyl, alkoxy or —NR⁵⁸R⁵⁹radical,

[0208] R⁵⁸ and R⁵⁹ represent, independently, a hydrogen atom or an alkylradical, or R⁵⁸ and R⁵⁹ together with the nitrogen atom to which theyare attached form an optionally substituted heterocycle;

[0209] p being an integer comprised between 0 and 6;

[0210] Het_(a) represents a heterocycle,

[0211] as well as addition salts with mineral and organic acids or withmineral and organic bases of said compounds of general formula (I),

[0212] for the preparation of medicaments for the treatment ofpathologies where calpains and/or reactive oxygen species are involved.

[0213] A more particular subject of the invention is the use ofcompounds of formula (I_(a)) as defined above, for the preparation ofmedicaments for the treatment of pathologies involving reactive oxygenspecies. A more particular subject of the invention is also the use ofcompounds of formula (I_(a)) as defined above, for the preparation ofmedicaments for the treatment of pathologies involving reactive oxygenspecies and calpains. The invention therefore relates to the use ofcompounds of formula (I_(a)) as defined above, for the preparation ofmedicaments for the treatment of pathologies such as inflammatory andimmunological diseases, cardiovascular and cerebrovascular diseases,disorders of the central or peripheral nervous system, osteoporosis,muscular dystrophy, proliferative diseases, cataracts, organtransplants, auto-immune and viral diseases, cancer, and all pathologiescharacterized by an excessive production of ROS's and/or the activationof calpains.

[0214] A more particular subject of the invention is the use ofcompounds of formula (I_(a)) as defined above, characterized in that Hetrepresents a monocyclic radical containing 1 to 2 heteroatoms chosenfrom O and N. Preferentially, Het represents tetrahydrofuran, dioxolane,pyrrolidine, 1,3-oxazolidine, and R¹ represents the hydrogen atom, the—OR³ or oxo radical.

[0215] A more particular subject of the invention is the use ofcompounds of formula (I_(a)) as defined above, characterized in that Xrepresents —(CH₂)_(n)—, —(CH₂)_(n)—CO—, —O—(CH₂)_(n)—CO—,—CO—N(R⁴⁵)—CO—, —CO—, —N(R⁴⁵)—CO—(CH₂)_(n)—CO—,—N(R⁴⁵)—CO—C(R⁴⁶R⁴⁷)—CO—, —N(R⁴⁵)—(CH₂)_(n)—CO—,—N(R⁴⁵)—CO—NH—C(R⁴⁶R⁴⁷)—CO— or —CO—N(R⁴⁵)—C(R⁴⁶R⁴⁷)—CO andpreferentially when R⁴⁵ and R⁴⁷ represent the hydrogen atom, R⁴⁶represents the hydrogen atom, an alkyl or phenyl radical, D representsthe phenylene radical and Z represents the thiazole radical.

[0216] A more particular subject of the invention is the use ofcompounds of formula (I_(a)) as defined above characterized in that R²represents a hydrogen atom or an aralkyl radical, and preferably thebenzyl radical.

[0217] A more particular subject of the invention is the use ofcompounds of formula (I_(a)) as defined above characterized in that Arepresents either A1 with W representing the sulphur atom; or A′1; or A2together with R²⁴, R²⁵ and R²⁶ which represent, independently, ahydrogen or an alkyl radical and Q which represents —OR³³; or A3together with T representing the —(CH₂)₂— radical; or A4 together with Trepresenting the —(CH₂)— radical. Preferably, A represents a radicalchosen from

[0218] A more particular subject of the invention is also the use asdefined above, of compounds of formula (I_(a)) as described in theexamples and preferentially the compounds which correspond to one of thefollowing formulae:

[0219](2R)-6-hydroxy-N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;

[0220]N-1-(4-anilinophenyl)-N-4-[(3S)-2-hydroxytetrahydro-3-furanyl]succinamide;

[0221](3S)-3-{[4-(4-anilinoanilino)-4-oxobutanoyl]amino}tetrahydro-2-furanylacetate;

[0222]N-1-(4-anilinophenyl)-N-4-[(1S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl]succinamide;

[0223]N-1-(4-anilinophenyl)-N-3-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenylmalonamide;

[0224] 3-(4-anilinoanilino)tetrahydro-2-furanol;

[0225]N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;

[0226](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)-amino]pentanoyl}amino)tetrahydro-2-furanylacetate;

[0227]N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;

[0228]N-[4-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;

[0229]N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;

[0230](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylpivalate;

[0231](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl3,3-dimethylbutanoate;

[0232](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylbenzoate;

[0233](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylphenylacetate;

[0234](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl(2S)-2-(dimethylamino)-3-phenylpropanoate;

[0235](3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl4-morpholinecarboxylate;

[0236]N-{(1S)-3-methyl-1-[(3-oxo-1-pyrrolidinyl)carbonyl]butyl}-10H-phenothiazine-2-carboxamide;

[0237]2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-hydroxytetrahydro-3-furanyl]acetamide;

[0238]N¹-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenyl-N³-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide;

[0239] N-(2-anilinophenyl)-N′-[(3S)-2-hydroxytetrahydro-3-furanyl]urea;

[0240]N¹-[(3S)-2-hydroxytetrahydro-3-furanyl]-N²-(1-propyl-2,3-dihydro-1H-indol-5-yl)ethanediamide;

[0241](2R)-N-[(1S)-1-(1,3-dioxolan-2-yl)-2-phenylethyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;

[0242] N-[(3S)-2-hydroxytetrahydro-3-furanyl]-5-indolinecarboxamide.

[0243] The non-commercial synthesis intermediates of formula (II), (III)and (V) can be prepared according to the different synthesis routesbelow:

1) Synthesis of Intermediates (II)

[0244] The carboxylic acids of general formula (II), in which A, X, D,n, R⁴⁵, R⁴⁶ and R⁴⁷ are as described above, are accessible from thefollowing synthetic diagrams:

[0245] 1.1) Starting from A—NH(R⁴⁵):

[0246] The preparation of carboxylic acids of general formula (II) canbe carried out, in this case, from 3 different acid-ester derivatives(II.2), (II.4) and (II.6):

[0247] The condensation of the anilines of general formula (II.1) withcommercial acid-esters (Alk=Alkyl) of general formula (II.2), Diagram1.1, is carried out by standard peptide condensation. The carboxamideobtained intermediately (II.3) is then saponified in order to producethe carboxylic acids of general formula (II). The synthesis of theintermediates of general formula (II.1) is described below.

[0248] The synthesis of the carboxylic acids of general formula (II) canalso be carried out by condensation of the anilines of general formula(II.1) with the acid-ester derivatives of general formula (II.4) underthe conditions described previously. This condensation is followed bystandard saponification in order to produce acids of general formula(II). The synthesis of intermediates of general formula (II.4) isdescribed below.

[0249] The condensation of the amines of general formula (II.1) with thecommercial aromatic acids of general formula (II.6), under standardpeptide synthesis conditions described already, after saponification ofthe intermediates of general formula (II.7) also leads to carboxylicacids of general formula (II).

[0250] Alternatively, the carboxylic acids of general formula (II) arealso accessible by opening cyclic anhydrides such as for examplesuccinic anhydride, using the amines of general formula (II.1) accordingto an experimental protocol described in the literature (J. Amer. Chem.Soc. (1951) 73, 4007).

[0251] 1.1.1) Preparation of Intermediates (II.1):

[0252] The non-commercial anilines of general formula (II.1),derivatives of indoline or 1,2,3,4-tetrahydroquinoline, Diagram 1.1.1,in which T and R³⁸ are as defined above, can be prepared from thecorresponding nitro derivatives of general formula (II.1.1).6-nitro-1,2,3,4-tetrahydroquinoline is described in Can. J. Chem.(1952), 30, 720-722. Alkylation of the amine is carried out in astandard fashion using a strong base such as, for example, NaH, in apolar aprotic solvent such as, for example, DMF in the presence of ahalogenated derivative R³⁸-Hal, such as for example3-dimethylaminopropane chloride or benzyl bromide. The nitro derivativeof general formula (II.1.2) obtained intermediately is then reduced, forexample, by Raney Nickel in the presence of hydrazine hydrate in orderto produce the anilines of general formula (II.1).

[0253] Moreover, certain non-commercial derivatives of phenylenediaminesof general formula (II.1) can be prepared according to Farmaco (1951) 6,713-717.

[0254] In the particular case where A is a phenolic derivative (A=A2),the anilines of general formula (II.1) are obtained by hydrogenation, inthe presence of Pd/C, of the nitrophenol derivative precursors. Thenitrated derivatives of di-alkyl phenols are accessible according to themethods described in J. Org. Chem. (1968) 33 (1), 223-226 or J. Med.Chem. (1998), 41, 1846-1854.

[0255] The intermediates of general formula (II.1) in which A′1 is adiphenylamine are accessible via the methods described in the literature(Synthesis (1990) 430; Indian J. Chem. (1981) 20B, 611-613; J. Med.Chem. (1975) 18 (4), 386-391) which involve the reduction of anitrodiphenylamine intermediate. Reduction of the nitro function iscarried out in a standard fashion by hydrogenation in the presence of acatalytic quantity of Pd/C in order to access the aminodiphenylamines ofgeneral formula (II.1).

[0256] When A is a carbazole derivative (W then represents a directbond), the methods for preparing the aminocarbazoles of general formula(II.1) involve the synthesis of a nitrocarbazole intermediate. Thesemethods are described in Pharmazie (1993) 48 (11), 817-820; Synth.Commun. (1994) 24(1), 1-10; J. Org. Chem. (1980) 45, 1493-1496; J. Org.Chem. (1964) 29 (8), 2474-2476; Org. Prep. Proced. Int. (1981) 13 (6),419-421 or J. Org. Chem. (1963) 28, 884. Reduction of the nitro functionof the nitrocarbazole intermediates is, in this case, preferably carriedout using hydrazine hydrate in the presence of Raney Nickel.

[0257] The intermediates of general formula (II.1) in which A is aphenothiazine derivative (W represents a sulphur atom), are accessiblevia methods in the literature which involve the synthesis of anitrophenothiazine derivative. In particular 3-nitrophenothiazine isdescribed in J. Org. Chem. (1972) 37, 2691. The reduction of the nitrofunction in order to access the aminophenothiazines of general formula(II.1) is carried out in a standard fashion by hydrogenation in thepresence of a catalytic quantity of Pd/C in a solvent such as ethanol.

[0258] 1.1.2) Preparation of Intermediates (II.4):

[0259] The acid-esters of general formula (II.4), Diagram 1.1.2, can beprepared from the commercial diesters of general formula (II.4.1)according to a method described in the literature (Tetrahedron Asymmetry(1997) 8 (11), 1821-1823).

[0260] 1.2) Starting from A—CO₂H:

[0261] The carboxylic acid intermediates of general formula (II) arealso accessible via the condensation of the carboxylic acids of generalformula (II.8) with the commercial amino-esters of general formula(II.9A) or (II.9B), Diagram 1.2, during a peptide synthesis stagedescribed previously. The carboxamides obtained intermediately (II.10A)and (II.10B) are then saponified in order to produce the carboxylicacids of general formula (II).

[0262] 1.2.1) Preparation of Intermediates (II.8):

[0263] The carboxylic derivatives of general formula (II.8), which arenot commercially accessible, can be prepared from the literature (e.g.:J. Org. Chem. (1961) 26, 1221-1223; Acta Chem. Scandinavica (1973) 27,888-890; Can. J. Chem. (1972) 50, 1276-1282; J. Med. Chem. (1992) 35(4),716-724; J. Org. Chem. (1989) 54, 560-569; J. Med. Chem. (1998) 41(2),148-156; Bull. Soc. Chim. Fr. (1960), 1049-1066)).

[0264] 1.3) Starting from A—OH or A—SH:

[0265] The acids of general formula (II) (Diagram 1.3) in which Xrepresents —O—(CH₂)_(n)—CO—, are prepared from the hydroquinones ofgeneral formula (II.11) obtained according to the literature (J. Chem.Soc. Perkin 1 (1981) 303-306). The condensation on commercial halogenesters of general formula (II.12) is carried out in the presence of abase such as, for example K₂CO₃, by heating in a polar solvent such as,for example, THF for at least 5 hours. The esters of general formula(II.13) intermediately obtained are then deprotected (in an acid mediumin the case of tert-butyl esters) in order to produce acids of generalformula (II).

[0266] The acids of general formula (II) in which X represents—S—(CH₂)_(n)—CO—, are prepared according to a method in the literature(J. Med. Chem. (1997) 40 (12), 1906-1918).

[0267] 1.4) Starting from A—CO₂H, when Z represents a heterocycle withV═S or O:

[0268] 1.4.a) In the case where Z represents an unsaturated heterocycle,the carboxylic acids of general formula (II), Diagram 1.4a, can beprepared from carboxylic acids of general formula (II.8).

[0269] The formation of the primary carboxamide of general formula(II.14) is carried out according to an experimental protocol describedin the literature (Synthesis (1989), 1, 37). By heating, between 50° C.and reflux of the solvent, for a time comprised between 1 and 15 hours,intermediate (II.14) in the presence of an alkyl bromopyruvate, theoxazoles (V═O) of general formula (II.16) are obtained. Alternatively,the thiazoles (V═S) of general formula (II.16), are accessible in twostages from the carboxamides of general formula (II.14). These, in thepresence of Lawesson's reagent in a solvent such as, for example,1,4-dioxane, lead in a standard fashion to the thiocarboxamides ofgeneral formula (II.15). The cyclization stage is then carried out inthe presence of alkyl bromopyruvate as described previously. Thecarboxylic acids of general formula (II) are finally obtained bydeprotection of the acid function under standard conditions.

[0270] 1.4.b) In the case where Z represents a saturated heterocycle,and in particular a thiazolidine, the carboxylic acids of generalformula (II), Diagram 1.4b, are also accessible from the carboxylicacids of general formula (II.8).

[0271] The preparation of the aldehydes of general formula (II.17) iscarried out in a standard fashion after activation of the acid functionof the intermediates of general formula (II.8) in the form of an esteror an alkylhydroxamate, in the presence of DIBAL or of LiAlH₄, accordingto the experimental protocols in the literature (e.g. J. Med. Chem.(1990) 33, 11-13). The reaction of these aldehydes with cystine in thepresence of acetate salts leads directly to the thiazolidines of generalformula (II.18) according to an experimental protocol described in J.Org. Chem. (1957) 22, 943-946. The amine of the thiazolidine ring isthen protected in the form of a carbamate (e.g. Boc) under standardconditions in the literature in order to produce the carboxylic acids ofgeneral formula (II).

[0272] 1.5) Starting from A—N(R⁴⁵)—CO—:

[0273] The carboxylic acids of general formula (II), in whichX=—N(R⁴⁵)—(CH₂)_(n)—CO— with n=0, are constituted by a chainfunctionalized by a urea, Diagram 1.5.

[0274] The synthesis of these ureas is carried out by condensation ofthe amines of general formula (II.1) with the aminoesters of generalformula (II.9) in the presence of triphosgene and a tertiary amineaccording to an experimental protocol described in the literature (J.Org. Chem. (1994), 59(7), 1937-1938) in order to produce theintermediates of general formula (II.19). The carboxylic acid of generalformula (II) is then obtained in a standard fashion by deprotection ofthe intermediate ester.

2) Synthesis of Intermediates (III)

[0275] The preparation of intermediates of general formula (III),Diagram 1.4, in which R² is as defined above and Y=—(CH₂)_(p)—, withp=0, is carried out from derivatives of N-Cbz aspartic acid of generalformula (III.1) access to which is described in the literature (J. Med.Chem. (1973) 16 (11), 1277-1280). By heating these intermediates in thepresence of trioxane and a catalytic quantity of PTSA under reflux of asolvent such as, for example, toluene, (Synthesis (1989) 7, 542-544) theoxazolidinone derivatives of general formula (III.2) are obtained.Reduction of the acid function is then carried out using B₂H₆.THF in THFas described in Chem. Pharm. Bull. (1995) 43 (10), 1683-1691 and leadsto alcohols of general formula (III.3). These are then treated in abasic medium, and intermediate (III.4) generated in this way is cyclizedusing a standard dehydration agent such as, for example,dicyclohexylcarbodiimide in order to obtain the substituted lactone ofgeneral formula (III.5). The intermediate of general formula (III) isobtained after cleavage of the benzyl carbamate using Pd/C under ahydrogen atmosphere.

3) Synthesis of Intermediates (V)

[0276] The intermediates of general formula (V) (Diagram 2.1), in whichA, X, Y, R⁵³ and R⁵⁴ are as described above, are prepared in a standardfashion by peptide condensation of the acids of general formula (II),described previously, with commercial amino-esters of general formula(V.1). Carboxylic acids of general formula (V) are obtained aftersaponification of the intermediate esters of general formula (V.2).

[0277] A subject of the invention is also, as new industrial products,and in particular as new industrial products intended for thepreparation of products of formula I, the products corresponding to oneof the following formulae:

[0278]N-1-(4-anilinophenyl)-N-4-[(3S)-2-oxotetrahydro-3-furanyl]succinamide;

[0279] methyl(2S)-2-{[4-(4-anilinoanilino)-4-oxobutanoyl]amino}-4-methylpentanoate;

[0280] N1-(4-anilinophenyl)-N4-[(1S)-1-formyl-3-methylbutyl]succinamide;

[0281] benzyl 3-(4-anilinoanilino)-3-oxo-2-phenylpropanoate;

[0282] 3-(4-anilinoanilino)-3-oxo-2-phenylpropanoic acid;

[0283]N-1-(4-anilinophenyl)-N-3-[(3S)-2-oxotetrahydro-3-furanyl]-2-phenylmalonamide;

[0284] 3-(4-anilinoanilino)dihydro-2(3H)-furanone;

[0285] methyl(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoate;

[0286] (2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoicacid;

[0287]N-[(1S)-3-methyl-1-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)butyl]-10H-phenothiazine-2-carboxamide;

[0288] ethyl 2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxylate;

[0289] 2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxylic acid;

[0290]N-[(3S)-2-oxotetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;

[0291] methyl 4-[(10H-phenothiazin-2-ylcarbonyl)amino]benzoate;

[0292] 4-[(10H-phenothiazin-2-ylcarbonyl)amino]benzoic acid;

[0293]N-[4-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;

[0294] methyl(2S)-4-methyl-2-[(10H-phenothiazin-1-ylcarbonyl)amino]pentanoate;

[0295] (2S)-4-methyl-2-[(10H-phenothiazin-1-ylcarbonyl)amino]pentanoicacid;

[0296]N-[(1S)-1-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;

[0297]N-[(1s)-1-(1,4-dioxa-7-azaspiro[4.4]non-7-ylcarbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;

[0298]2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-oxotetrahydro-3-furanyl]acetamide

[0299] 5-nitro-1-propylindoline;

[0300] 1-propyl-2,3-dihydro-1H-indol-5-ylamine;

[0301]3-oxo-2-phenyl-N-(1-propyl-2,3-dihydro-1H-indol-5-yl)-beta-alanine;

[0302]N¹-[(3S)-2-oxotetrahydro-3-furanyl]-2-phenyl-N³-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide;

[0303] N-(2-anilinophenyl)-N′-[(3S)-2-oxotetrahydro-3-furanyl]urea;

[0304] ethyl oxo[(1-propyl-2,3-dihydro-1H-indol-5-yl)amino]acetate;

[0305] oxo[(1-propyl-2,3-dihydro-1H-indol-5-yl)amino]acetic acid;

[0306] methyl(2S)-2-({[(2R)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]carbonyl}amino)-3-phenylpropanoate;

[0307](2R)-N-[(1S)-1-benzyl-2-oxoethyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;

[0308] tert-butyl 5-methyl 1,5-indolinedicarboxylate;

[0309] 1-(tert-butoxycarbonyl)-5-indolinecarboxylic acid;

[0310] tert-butyl5-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)-1-indolinecarboxylate;

[0311] tert-butyl5-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-1-indolinecarboxylate.

Experimental Part

[0312] The following examples are presented in order to illustrate theabove procedures and should in no event be considered as a limit to thescope of the invention.

EXAMPLE 1(2R)-6-hydroxy-N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide

[0313] 1.1)(2R)-6-hydroxy-2,5,7,8-tetramethyl-N-[(3S)-2-oxotetrahydro-3-furanyl]-3,4-dihydro-2H-chromene-2-carboxamide:

[0314] A solution of 1.82 g (7.27 mmoles) of (R)-Trolox and 1.18 g (7.27mmoles) of 1,1′-carbonyldiimidazole (CDI) in 15 ml of anhydrous THF isstirred for 1 hour at 23° C., before adding a solution of 1 g (7.27mmoles) of (S)-2-amino-4-butyrolactone hydrochloride and 1.27 ml (7.27mmoles) of N,N-diisopropylethylamine (DIEA) in 15 ml of anhydrous DMF.The reaction mixture is stirred for 15 hours at 23° C. and finallyconcentrated to dryness under vacuum. The residue is dissolved in 100 mlof AcOEt and the organic solution is washed successively with 50 ml of1N aqueous HCl, 50 ml of H₂O, 50 ml of a saturated aqueous solution ofNaHCO₃, 50 ml of H₂O and finally 50 ml of salt water. After drying overMgSO₄, the organic solution is filtered and concentrated to drynessunder vacuum. The residue is taken up in 50 ml of Et₂O, followed byagitating and filtering. After rinsing with 2×25 ml of Et₂O, the whitepowder obtained is dried under vacuum. Melting point: 195-196° C.

[0315] 1.2)(2R)-6-hydroxy-N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide:

[0316] 1.53 g (4.59 mmoles) of intermediate 1.1 in 75 ml of anhydrousTHF is dissolved in a three-necked flask, under an argon atmosphere. Themixture is cooled down to −78° C., before the introduction, dropwise,using an addition phial, of 18.4 ml (18.4 mmoles) of a 1M solution ofDIBAL in CH₂Cl₂. After stirring for 3 hours at −78° C., the reaction isstopped by the slow introduction of 10 ml of MeOH. Once it has risen to20° C., the reaction mixture is poured into 150 ml of a Rochelle saltsolution under vigorous stirring. Stirring is maintained until twophases appear. The mixture is decanted and the aqueous phase isreextracted twice with 50 ml of CH₂Cl₂. The organic phases are collectedand washed successively with 50 ml of H₂O and 50 ml of salt water. Afterdrying over MgSO₄ and filtration, the solvent is evaporated off undervacuum and the residue is purified on a silica column (eluent:Heptane/AcOEt: 2/8). A white powder is obtained.

[0317] Melting point 67-70° C.

[0318] Examples 2 to 11 illustrate compounds capable of being preparedaccording to the synthesis diagrams described previously.

EXAMPLE 22-[(3,5-di(tert-butyl)-4-hydroxyphenyl)sulphanyl]-N-(2-hydroxytetrahydro-3-furanyl)acetamideEXAMPLE 3N-1-(2-hydroxytetrahydro-3-furanyl)-N-4-(1-methyl-2,3-dihydro-1H-indol-5-yl)succinamideEXAMPLE 4N-1-(4-anilinophenyl)-N-3-(2-hydroxytetrahydro-3-furanyl)-2-isopropylmalonamideEXAMPLE 5N-1-(4-anilinophenyl)-N-3-(2-hydroxytetrahydro-3-furanyl)isophthalamideEXAMPLE 6N-1-(4-anilinophenyl)-N-4-(2-hydroxytetrahydro-3-furanyl)terephthalamideEXAMPLE 7N-1-(4-anilinophenyl)-N-2-(2-hydroxytetrahydro-3-furanyl)phthalamideEXAMPLE 8N-{1-[(4-benzyl-5-hydroxy-1,3-oxazolidin-3-yl)carbonyl]-2-methylpropyl}-6-hydroxy-2,5,7,8-tetramethyl-2-chromanecarboxamideEXAMPLE 9N-(4-anilinophenyl)-N′-{1-[(4-benzyl-5-hydroxy-1,3-oxazolidin-3-yl)carbonyl]-2-methylpropyl}ureaEXAMPLE 10N-{1-[(4-benzyl-5-oxo-1,3-oxazolidin-3-yl)carbonyl]-2-methylpropyl}-2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]acetamideEXAMPLE 116-hydroxy-2,5,7,8-tetramethyl-N-{2-methyl-1-[(3-oxo-1-pyrrolidinyl)carbonyl]propyl}-2-chromanecarboxamideEXAMPLE 12N-1-(4-anilinophenyl)-N-4-[(3S)-2-hydroxytetrahydro-3-furanyl]succinamide

[0319] 12.1) 4-(4-anilinoanilino)-4-oxobutanoic acid:

[0320] The experimental protocol used is the same as that described inJ. Amer. Chem. Soc. (1951) 73, 4007, starting fromN¹-phenyl-1,4-benzenediamine and succinic anhydride in order to producea pale grey-blue powder. Melting point: 175-176° C.

[0321] 12.2)N-1-(4-anilinophenyl)-N-4-[(3S)-2-oxotetrahydro-3-furanyl]succinamide:

[0322] 4-(4-anilinoanilino)-4-oxobutanoic acid (1.14 g, 4 mmoles) iscondensed with (S)-2-amino-4-butyrolactone hydrochloride (0.5 g, 3.6mmoles) in the presence of 0.54 g (4 mmoles) of HOBT, 1.53 g (8 mmoles)of EDC and 1.66 ml (11.9 mmoles) of triethylamine in 25 ml of dry DMF.The mixture is stirred for 15 hours before concentration to drynessunder vacuum. The evaporation residue is divided between 100 ml of AcOEtand 100 ml of a 1M aqueous solution of HCl. A precipitate appears whichis filtered on frit and rinsed successively with H₂O, AcOEt, Et₂O andCH₂Cl₂. 1.12 g of a light grey powder is obtained. Melting point:202-203° C.

[0323] 12.3)N-1-(4-anilinophenyl)-N-4-[(3S)-2-hydroxytetrahydro-3-furanyl]succinamide:

[0324] The experimental protocol used is identical to that described forintermediate 1.2. White powder. Melting point: 178-179° C.

EXAMPLE 13(3S)-3-{[4-(4-anilinoanilino)-4-oxobutanoyl]amino}tetrahydro-2-furanylacetate

[0325] Intermediate 12.3 (0.15 g, 0.4 mmole) is dissolved in 4 ml ofacetic anhydride in the presence of 10 mg (0.08 mmole) ofN,N-dimethyl-4-pyridinamine. The reaction mixture is stirred for 3 hoursat 20° C. The mixture is finally poured into 25 ml of ice-cold water andextraction is carried out twice using 25 ml of AcOEt. The organicsolution is washed successively with 20 ml of a 2M solution of citricacid, 20 ml of H₂O, 20 ml of a saturated solution of NaHCO₃ and finally20 ml of salt water. After drying over sodium sulphate, filtration andevaporation of the solvent, the residue is purified on a silica column(eluent: AcOEt). White powder. Melting point: 191-192° C.

EXAMPLE 14N-1-(4-anilinophenyl)-N-4-[(1S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl]succinamide

[0326] 14.1) methyl(2S)-2-{[4-(4-anilinoanilino)-4-oxobutanoyl]amino}-4-methylpentanoate:

[0327] The experimental protocol used is identical to that described forintermediate 12.2, with the methyl ester of L-Leucine replacing the(S)-2-amino-4-butyrolactone. Grey powder.

[0328] Melting point: 134-135° C.

[0329] 14.2)N¹-(4-anilinophenyl)-N⁴-[(1S)-1-formyl-3-methylbutyl]succinamide:

[0330] The experimental protocol used is identical to that described forintermediate 1.2 starting from intermediate 14.1. White powder. Meltingpoint: 128-129° C.

[0331] 14.3)N-1-(4-anilinophenyl)-N-4-[(1S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl]succinamide:

[0332] A mixture of 0.38 g (1 mmole) of intermediate 14.2, 0.06 ml (1.1mmole) of ethylene glycol and 20 mg of para-toluenesulphonic acid in 30ml of toluene is heated under reflux for 3 hours. After returning to 20°C., the mixture is diluted with 20 ml of AcOEt and this organic solutionis washed with H₂O followed by salt water. After drying over magnesiumsulphate, filtration and concentration to dryness under vacuum, theresidue is purified on a silica column (eluent: Heptane/AcOEt: 1/9).Cream powder. Melting point: 156-157° C.

EXAMPLE 15N-1-(4-anilinophenyl)-N-3-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenylmalonamide

[0333] 15.1) Benzyl 3-(4-anilinoanilino)-3-oxo-2-phenylpropanoate:

[0334] The experimental protocol used is the same as that described forintermediate 12.2, starting from N¹-phenyl-1,4-benzenediamine and3-(benzyloxy)-3-oxo-2-phenylpropanoic acid.

[0335] 15.2) 3-(4-anilinoanilino)-3-oxo-2-phenylpropanoic acid:

[0336] Intermediate 15.1 (1.4 g, 3.2 mmoles), dissolved in 30 ml of aCH₂Cl₂/EtOH mixture 2/1, is placed under a hydrogen atmosphere (1.5 bar)for 1 hour in the presence of 100 mg of 10% Pd/C. After elimination ofthe Pd/C by filtration, the filtrate is concentrated under vacuum andpurified on a silica column (eluent: Heptane/AcOEt: 1/1 to 0/1).Partially crystallized oil.

[0337] 15.3)N-1-(4-anilinophenyl)-N-3-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenylmalonamide:

[0338] The preparation of this compound is carried out in two stages,starting from intermediate 15.2, according to the experimental protocolsdescribed for the successive synthesis of intermediates 12.2 and 12.3.Light beige powder. Melting point: 86-86.5° C.

EXAMPLE 16 3-(4-anilinoanilino)tetrahydro-2-furanol

[0339] 16.1) 3-(4-anilinoanilino)dihydro-2(3H)-furanone:

[0340] A mixture of 1.84 g (10 mmoles) of N¹-phenyl-1,4-benzenediamineand 0.41 ml (5 mmoles) of α-bromo-γ-butyrolactone in 20 ml ofacetonitrile is heated under reflux for 5 hours. After returning to 20°C., the precipitate which appears during the reaction(N¹-phenyl-1,4-benzenediamine hydrobromide) is filtered and rinsed with20 ml of acetonitrile. The filtrate is concentrated to dryness undervacuum and the residue is purified on a silica column (eluent:Heptane/AcOEt: 1/1 to 4/6). Beige powder. Melting point: 142.5-143° C.

[0341] 16.2)3-(4-anilinoanilino)tetrahydro-2-furanol:

[0342] The experimental protocol used is the same as that described forintermediate 1.2, starting from intermediate 16.1. Off-white powder.Melting point: 139-139.4° C.

EXAMPLE 17N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide

[0343] 17.1) methyl(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoate:

[0344] 4.6 ml (33 mmoles) of triethylamine is added to a solution of1.82 g (10 mmoles) of L-Leucine methyl ester hydrochloride, 2.43 g (10mmoles) of 10H-phenothiazine-2-carboxylic acid (J. Med. Chem.(1998) 41(2), 148-156), 1.48 g (11 mmoles) of HOBT and 4.21 g (22 mmoles) of EDCin 30 ml of anhydrous DMF. The reaction mixture is stirred for 15 hours.After evaporation of the solvent under vacuum, the residue is dividedbetween 100 ml of AcOEt and 50 ml of a 1M solution of HCl. The organicphase is decanted and washed successively with 50 ml of H₂O, 50 ml of asaturated solution of NaHCO₃ and 50 ml of salt water. The organicsolution is dried over magnesium sulphate, filtered and concentrated todryness under vacuum. The evaporation residue is taken up in Et₂O andfiltered. Yellow powder (71%). Melting point: 160.5-161° C.

[0345] 17.2)(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoic acid:

[0346] A solution of 0.44 g (11 mmoles) of LiOH, H₂O in 20 ml of H₂O isadded in one go to a solution of 1.85 g (5 mmoles) of intermediate 17.1in 20 ml of THF. The reaction mixture is stirred for 1 hour 30 minutesat 20° C. The mixture is cooled down using an ice bath before theaddition of a concentrated aqueous solution of HCl until an acid pH isobtained. After dilution with 100 ml of AcOEt and stirring, the organicphase is decanted.

[0347] This is then washed with 20 ml of a 1M aqueous solution of HClfollowed by 20 ml of salt water. The organic solution is dried oversodium sulphate, filtered and concentrated to dryness under vacuum.Yellow-green powder. The product is used as it is in the followingstage.

[0348] 17.3)N-[(1S)-3-methyl-1-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)butyl]-10H-phenothiazine-2-carboxamide:

[0349] The experimental protocol used is the same as that described forintermediate 12.2, with intermediate 17.2 replacing intermediate 12.1.Yellow powder. Melting point: 151-152° C.

[0350] 17.4)N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide:

[0351] The experimental protocol used is the same as that described forintermediate 1.2, with intermediate 17.3 replacing intermediate 1.1.Yellow powder. Melting point: 100-101° C.

EXAMPLE 18(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)-amino]pentanoyl}amino)tetrahydro-2-furanylacetate

[0352] The experimental protocol used is the same as that described forExample 13, starting from intermediate 17.4. The two diastereoisomers18.1 and 18.2 are separated by chromatography on a silica column(eluent: Heptane/AcOEt: 1/1).

[0353] 18.1)(2R,3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]-pentanoyl}amino)tetrahydro-2-furanylacetate:

[0354] Pale yellow powder. Melting point: 199-201° C.

[0355] 18.2)(2S,3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylacetate:

[0356] Pale yellow powder. Melting point: 205-208° C.

EXAMPLE 19N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide

[0357] 19.1) 10H-phenothiazine-2-carbothioamide:

[0358] A reaction mixture comprising 3.4 g (14 mmoles) of10H-phenothiazine-2-carboxamide (J. Org. Chem. (1961) 26, 1138-1143) and3.4 g (8.4 mmoles) of Lawesson's reagent in solution in 40 ml of1,4-dioxane to which 20 ml of pyridine is added is heated at 110° C. for1 hour 30 minutes. The brown solution is then concentrated under vacuumand the residue is diluted in 200 ml of AcOEt and 100 ml of H₂O. Afterstirring and decanting, the organic phase is washed successively with100 ml of a 1N aqueous solution of HCl and 100 ml of salt water. Afterdrying over sodium sulphate, filtration and evaporation of the solventunder vacuum, an orange powder is obtained. This powder is washed withEt₂O, the filtrate is eliminated, and extraction is carried out withacetone. The acetonic filtrate is then concentrated under vacuum and theevaporation residue is then purified on a silica column (eluent:Heptane/AcOEt: 1/1 to 4/6). Orange powder. Melting point: 208-209° C.

[0359] 19.2) ethyl 2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxylate:

[0360] 2.09 ml (16.5 mmoles) of ethyl bromopyruvate is added to asuspension of 1.43 g (5.53 mmoles) of intermediate 19.1 in 70 ml ofabsolute EtOH. The reaction mixture is then heated under reflux for 1hour 30 minutes. After concentration to dryness under vacuum, the blackresidue obtained is washed with Et₂O before being placed at the top of achromatography column (eluent: Heptane/AcOEt/THF: 6/4/0 to pure THF).Yellow powder (83%).

[0361] 19.3) 2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxylic acid:

[0362] A solution of intermediate 19.2 (1.62 g, 4.57 mmoles) in 50 ml ofTHF is cooled down to 0° C. before the addition in one portion of asolution of 300 mg (7.3 mmoles) of NaOH in 30 ml H₂O. Stirring iscontinued for 15 hours at 20° C. before the reaction mixture isacidified, at 0° C., with an aqueous solution of concentrated HCl. Theproduct is then extracted using 100 ml of AcOEt and the organic solutionis washed with 25 ml of H₂O followed by salt water. After drying oversodium sulphate, filtration and concentration under vacuum, the residueis purified on a silica column (eluent: CH₂Cl₂/MeOH: 8/2 to 1/1). Yellowpowder.

[0363] 19.4)N-[(3S)-2-oxotetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide:

[0364] The experimental protocol used is the same as that described forintermediate 12.2, with intermediate 19.3 replacing intermediate 12.1.Yellow powder. Melting point: 277-277.5° C.

[0365] 19.5)N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide:

[0366] The experimental protocol used is the same as that described forintermediate 1.2, with intermediate 19.4 replacing intermediate 1.1.Yellow powder. Melting point: 189-190° C.

EXAMPLE 20N-[4-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide

[0367] 20.1) 4-[(10H-phenothiazin-2-ylcarbonyl)amino]benzoic acid:

[0368] The experimental protocol used is the same as that described forthe syntheses of intermediates 17.1 and 17.2, with methyl4-aminobenzoate acid replacing L-Leucine methyl ester.

[0369] 20.2)N-[4-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide:

[0370] The experimental protocol used is the same as that described forthe synthesis of intermediate 12.2, with intermediate 20.1 replacing the4-(4-anilinoanilino)-4-oxobutanoic acid. Yellow-green powder. Meltingpoint: 284-285° C.

[0371] 20.3)N-[4-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide:

[0372] The experimental protocol used is the same as that described forintermediate 1.2, with intermediate 20.2 replacing intermediate 1.1.Dark yellow powder. Melting point: 234-235° C.

EXAMPLE 21N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide

[0373] The experimental protocol used is identical to that described forcompound 17, with 10H-phenothiazine-1-carboxylic acid replacing10H-phenothiazine-2-carboxylic acid. Yellow powder. Melting point:99-101° C.

EXAMPLE 22(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylpivalate

[0374] 0.14 ml of 2,2-dimethylpropanoyl chloride is added dropwise to asolution of 0.45 g 1.02 mmole) of intermediate 17.4 and 0.28 ml (2.04mmoles) of Et₃N in 20 ml of CH₂Cl₂ cooled down to 0° C. The reactionmixture is then stirred for 24 hours at 22° C. After dilution with 50 mlof CH₂Cl₂, the organic solution is washed with 20 ml of water followedby 20 ml of salt water, dried over MgSO₄, filtered and concentrated todryness under vacuum. The product is finally purified by chromatographyon a silica column (eluent: Heptane/AcOEt: 1/1). Pale yellow solid.Melting point: 107-109° C.

EXAMPLE 23(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl3,3-dimethylbutanoate

[0375] The experimental protocol used is the same as that described forExample 22, starting from intermediate 17.4 and 3,3-dimethylbutanoylchloride. Yellow solid. Melting point: 111-113° C.

EXAMPLE 24(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylbenzoate

[0376] The experimental protocol used is the same as that described forExample 22, starting from intermediate 17.4 and benzoyl chloride. Paleyellow solid. Melting point: 193-195° C.

EXAMPLE 25(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylphenylacetate

[0377] The experimental protocol used is the same as that described forExample 22, starting from intermediate 17.4 and phenylacetyl chloride.Yellow solid. LC-MS: MH⁺=560.2.

EXAMPLE 26(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl(2S)-2-(dimethylamino)-3-phenylpropanoate

[0378] 0.22 g (1.13 mmole) of (2S)-2-(dimethylamino)-3-phenylpropanoicacid and 0.23 g (1.13 mmole) of 1,3-dicylohexylcarbodiimide are added toa solution of 0.5 g (1.13 mmole) of intermediate 17.4 in 2 ml of CH₂Cl₂.After stirring for 72 hours at 22° C., the precipitate is filtered andwashed with 10 ml of CH₂Cl₂. The filtrate is then washed with asaturated solution of NaHCO₃ (10 ml) followed by 10 ml of water and 10ml of salt water. The organic solution is dried over MgSO₄, filtered andconcentrated to dryness. The evaporation residue is purified on a silicacolumn (eluent: AcOEt). Yellow solid. LC-MS: MH⁺=617.2.

EXAMPLE 27(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl4-morpholinecarboxylate

[0379] The experimental protocol used is the same as that described forExample 22, starting from intermediate 17.4 and morpholinechloroformate. Yellow solid. Melting point: 165-167° C.

EXAMPLE 28N-{(1S)-3-methyl-1-[(3-oxo-1-pyrrolidinyl)carbonyl]butyl}-10H-phenothiazine-2-carboxamide

[0380] 28.1)N-[(1S)-1-(1,4-dioxa-7-azaspiro[4.4]non-7-ylcarbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide:

[0381] 0.23 g (1.76 mmole) of 1,4-dioxa-7-azaspiro[4.4]nonane (J. Med.Chem. (1992) 35 (8), 1392-1398), 0.26 g (1.93 mmole) of HOBT, 0.74 g(3.86 mmoles) of EDC and finally 0.54 ml (3.86 mmoles) of Et₃N are addedsuccessively to a solution of 0.62 g (1.76 mmole) of intermediate 17.2in 30 ml of CH₂Cl₂. The reaction mixture is stirred for 15 hours at 22°C. After dilution with 20 ml of water and stirring, the organic phase isdecanted and washed successively with 20 ml of water and 20 ml of saltwater. The organic solution is finally dried over MgSO₄, filtered andconcentrated to dryness. The evaporation residue is purified on a silicacolumn (eluent: Heptane/AcOEt: 1/1). Yellow solid. Melting point: 75-77°C.

[0382] 28.2)N-{(1S)-3-methyl-1-[(3-oxo-1-pyrrolidinyl)carbonyl]butyl}-10H-phenothiazine-2-carboxamide:

[0383] A solution of 0.28 g (0.6 mmole) of intermediate 28.1 in 14 ml ofCH₃OH and 10 ml of 8% H₂SO₄ is heated for 7 hours at 60° C. The reactionmixture is finally diluted with 20 ml of water and 30 ml of AcOEt. Afterstirring and decanting, the organic phase is washed successively with 20ml of a 1M solution of NaHCO₃ and 20 ml of salt water. The organicsolution is finally dried over Na₂SO₄, filtered and concentrated todryness. The evaporation residue is purified on a silica column (eluentHeptane/AcOEt: 1/1). Yellow solid. LC-MS: MH⁺=424.3.

EXAMPLE 292-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-hydroxytetrahydro-3-furanyl]acetamide

[0384] 29.1) 2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]acetic acid:

[0385] 3.6 ml (46 mmol) of trifluoroacetic acid is added to a solutionof 1.56 g (4.64 mmol) of tert-butyl2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]acetate (prepared according to J.Heterocycl. Chem. (1994) 31, 1439-1443) in 20 ml of dichloromethane. Thereaction mixture is stirred for 1 hour, concentrated under vacuum andthe residue is dissolved in 50 ml of Et₂O. The organic solution isextracted twice with 25 ml of a saturated solution of NaHCO₃, theaqueous phase is then washed with 25 ml of Et₂O. The basic aqueoussolution is then acidified, at 0° C., with a saturated solution of KHSO₄and finally the expected product is extracted twice using 25 ml of Et₂O.The organic solution is dried over sodium sulphate, filtered andconcentrated under vacuum in order to produce a yield of 70% of a whitepowder. Melting point: 172-173° C.

[0386] 29.2)2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-oxotetrahydro-3-furanyl]acetamide:

[0387] The experimental protocol used is the same as that described forintermediate 12.2, starting from intermediate 29.1. White solid. Meltingpoint: 162.5-163° C.

[0388] 29.3)2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-hydroxytetrahydro-3-furanyl]acetamide:

[0389] The experimental protocol used is the same as that described forintermediate 1.2, starting from intermediate 29.2. White solid. Meltingpoint: 133.5-134° C.

EXAMPLE 30N¹-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenyl-N³-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide

[0390] 30.1) 5-nitro-1-propylindoline:

[0391] 0.51 g (12.79 mmoles) of 60% NaH is added, at 20° C., byportions, to a solution of 2 g (12.18 mmoles) of 5-nitroindoline in 16ml of anhydrous DMF. After stirring for a further 30 minutes, 2.32 ml(25.58 mmoles) of 1-bromopropane is added dropwise. Stirring ismaintained overnight and the reaction mixture is finally diluted with 50ml of water and 50 ml of AcOEt. After stirring and decanting, theorganic phase is successively washed with 25 ml of water and 25 ml ofsalt water, dried over Na₂SO₄, filtered and concentrated to drynessunder vacuum. The evaporation residue is then purified on a silicacolumn (eluent: Heptane/AcOEt: 9/1). Orange oil.

[0392] 30.2) 1-propyl-2,3-dihydro-1H-indol-5-ylamine:

[0393] Approximately 400 mg of Raney nickel is added to a mixture of3.28 g (15.9 mmol) of 5-nitro-1-propylindoline and 4 ml (80 mmol) ofhydrazine hydrate in 60 ml of absolute ethanol. The reaction mixture isheated under reflux for 5 hours. After returning to 23° C., a littlesilica is added to the flask and the solvent is evaporated off undervacuum. The evaporation residue is placed directly at the top of achromatography column. The expected product is eluted using aHeptane/AcOEt mixture (1/9). A black oil is obtained which is useddirectly in the following stage.

[0394] 30.3)N¹-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenyl-N³-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide:

[0395] The experimental protocol used is the same as that described forExample 15, starting from intermediate 30.2. Yellow solid. LC-MS:MH⁺=424.2.

EXAMPLE 31N-(2-anilinophenyl)-N′-[(3S)-2-hydroxytetrahydro-3-furanyl]urea

[0396] 31.1)N-(2-anilinophenyl)-N′-[(3S)-2-oxotetrahydro-3-furanyl]urea:

[0397] A solution of 1.48 g (8.15 mmoles) of (S)-2-amino-4-butyrolactonehydrobromide and 3.12 ml (17.9 mmoles) of diisopropylethylamine in 80 mlof anhydrous CH₂Cl₂ is added slowly (4 hours) into a three-necked flaskcontaining a solution of 0.89 g (3 mmoles) of triphosgene in 45 ml ofanhydrous CH₂Cl₂, under an inert atmosphere. After stirring for afurther 15 minutes, a solution of 1.5 g (8.15 mmoles) ofN¹-phenyl-1,2-benzenediamine and 3.12 ml (17.9 mmoles) ofdiisopropylethylamine in 45 ml of anhydrous CH₂Cl₂ is added in one go.The reaction mixture is then heated for 5 hours at 60° C. Afterconcentration to dryness under vacuum, the residue is divided between 50ml of AcOEt and 50 ml of water. After stirring and decanting, theorganic phase is washed successively with 50 ml of water and 50 ml ofsalt water. The organic solution is then dried over Na₂SO₄, filtered andconcentrated under vacuum. The evaporation residue is then purified on asilica column (eluent: Heptane/AcOEt: 1/2). Pink solid.

[0398] Melting point: 63-65° C.

[0399] 31.2)N-(2-anilinophenyl)-N′-[(3S)-2-hydroxytetrahydro-3-furanyl]urea:

[0400] The experimental protocol used is the same as that described forintermediate 1.2, starting from intermediate 31.1. Pale pink solid.LC-MS: MH⁺=314.3.

EXAMPLE 32N¹-[(3S)-2-hydroxytetrahydro-3-furanyl]-N²-(1-propyl-2,3-dihydro-1H-indol-5-yl)ethanediamide

[0401] The experimental protocol used is the same as that described forExample 30, with ethyl chloro(oxo)acetate being used instead of3-(benzyloxy)-3-oxo-2-phenylpropanoic acid. Pale yellow solid. Meltingpoint: 120-122° C.

EXAMPLE 33(2R)-N-[(1S)-1-(1,3-dioxolan-2-yl)-2-phenylethyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide

[0402] The experimental protocol used is the same as that described forExample 14, with (R)-Trolox being used instead of intermediate 12.1 andthe methyl ester of L-phenylalanine replacing the L-Leucine methylester. Yellow oil. LC-MS: MH⁺=426.2.

EXAMPLE 34 N-[(3S)-2-hydroxytetrahydro-3-furanyl]-5-indolinecarboxamide

[0403] 34.1) tert-butyl 5-methyl 1,5-indolinedicarboxylate:

[0404] 1.26 g (5.8 mmoles) of di-tert-butyldicarbonate and 0.80 ml (5.8mmoles) of Et₃N are added successively at 20° C. to a solution of 0.85 g(4.8 mmoles) of methyl 5-indolinecarboxylate (J Heterocycl Chem (1993)30 (4), 1133-1136) in 15 ml of CH₂Cl₂. The reaction mixture is stirredfor 20 hours and concentrated to dryness under vacuum. The residue isdivided between 50 ml of AcOEt and 25 ml of water. After stirring anddecanting, the organic phase is washed with 25 ml of salt water, driedover MgSO₄, filtered and concentrated to dryness under vacuum. Thepowder obtained is suspended in heptane, stirred and filtered in orderto produce a white solid with a yield of 73%.

[0405] Melting point=107-107.5° C.

[0406] 34.2) 1-(tert-butoxycarbonyl)-5-indolinecarboxylic acid:

[0407] A solution of 0.97 g (3.49 mmoles) of intermediate 34.1 and of0.16 g (3.84 mmoles) of LiOH in a mixture of 20 ml of THF and 20 ml ofwater is stirred for 24 hours, at 20° C. The reaction mixture is thencooled down using an ice bath, acidified using a 1M KHSO₄ solution anddiluted with 50 ml of AcOEt. The organic phase is then decanted, washedwith 25 ml of salt water, dried over MgSO₄, filtered and concentrated todryness under vacuum. A white solid is obtained (92%) which is used asit is in the following stage.

[0408] 34.3) tert-butyl5-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)-1-indolinecarboxylate:

[0409] The experimental protocol used is the same as that described forintermediate 12.2, with intermediate 34.2 replacing intermediate 12.1.White solid. Melting point: 172.5-173° C.

[0410] 34.4) tert-butyl5-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-1-indolinecarboxylate:

[0411] The experimental protocol used is the same as that described forintermediate 1.2, with intermediate 34.3 replacing intermediate 1.1.White solid. Melting point: 141-141.5° C.

[0412] 34.5)N-[(3S)-2-hydroxytetrahydro-3-furanyl]-5-indolinecarboxamide:

[0413] 6 ml (24 mmoles) of a 4N solution of HCl in dioxane is addeddropwise to a solution of 0.4 g (1.15 mmoles) of intermediate 34.4 in 10ml of CH₂Cl₂, cooled down using an ice bath. After stirring for 2 hoursat 20° C., the reaction mixture is concentrated to dryness under vacuum.The residue is dissolved in 20 ml of water and the aqueous solution iswashed successively with 20 ml of AcOEt and 20 ml of CH₂Cl₂. The aqueousphase is then rendered basic by the addition of a saturated solution ofNa₂CO₃ and the product is finally extracted twice using 20 ml of AcOEt.The organic solution is dried over MgSO₄, filtered and concentratedunder vacuum. The evaporation residue is purified on a silica column(eluent: CH₂Cl₂/Acetone: 1/1). White solid. LC-MS: MH⁺=249.2.

[0414] Examples 35 to 37 illustrate compounds capable of being preparedaccording to the synthesis diagrams described previously.

EXAMPLE 35(2S)-2-{[(4-anilinoanilino)carbonyl]amino}-N-[(3S)-2-hydroxytetrahydro-3-furanyl]-4-methylpentanamideEXAMPLE 36(2S)-2-({[(1-benzyl-2,3-dihydro-1H-indol-5-yl)amino]carbonyl}amino)-N-[(3S)-2-hydroxytetrahydro-3-furanyl]-4-methylpentanamideEXAMPLE 37(2S)-N-[(3S)-2-hydroxytetrahydro-3-furanyl]-4-methyl-2-[({[1-(1-naphthhylmethyl)-2,3-dihydro-1H-indol-5-yl]amino}carbonyl)amino]pentanamidePharmacological Study of the Products of the Invention

[0415] Study of the Effects on Porcine Calpain I:

[0416] The method used is that described by Mallya et al. (Biochemicaland biophysical research communications 248 293-296 (1998)). The calpainin vitro activity is determined by measuring the fluorescence due to thedegradation of an artificial substrate of the Suc-LY-AMC enzyme(Suc-Leu-Tyr-aminomethylcoumarin). The aminomethylcoumarin releasedfluoresces at 460 nm under excitation at 380 nm. The inhibitors testedare dissolved in DMSO at 40 times the final concentration. 5 μl ofsolution is deposited in a 96-well plate with black walls. 175 μl/wellof reaction buffer containing calpain I and its substrate are thenadded. The reaction is started by adding 20 μl of CaCl₂ 50 mM. Theplates are incubated at 25° C. and the fluorescence (380 nm excitationand 460 nm transmission) is read after 30 minutes using a microplatereader (Victor, Wallack). The IC₅₀'s are determined by calculating theproduct fluorescence/DMSO control fluorescence ratio. Composition of theenzymatic reaction buffer: Tris-HCl 50 mM pH 7.5, NaCl 50 mM, EDTA 1 mM,EGTA 1 mM, b-Mercaptoethanol 5 mM, Suc-LY-AMC 1 mM (Bachem, ref. 1-1355)and 2.5 U/ml Calpain I (porcine erythrocytes, Calbiochem ref 208712).).In this test, the IC₅₀ value of certain compounds according to theinvention is lower than 5 μM.

[0417] Study of the Effects on Lipidic Peroxidation in the CerebralCortex of the Rat:

[0418] The inhibitory activity of the products of the invention isdetermined by measuring their effects on the degree of lipidicperoxidation, determined by the concentration of malondialdehyde (MDA).The MDA produced by the peroxidation of unsaturated fatty acids is agood indicator of lipidic peroxidation (H Esterbauer and KH Cheeseman,Meth. Enzymol. (1990) 186: 407-421). Male Sprague Dawley rats weighing200 to 250 g (Charles River) were sacrificed by decapitation. Thecerebral cortex is removed, then homogenised with a Thomas potter in aTris-HCl buffer, 20 mM, pH=7.4. The homogenate is centrifuged twice at50,000 g for 10 minutes at 4° C. The pellet is kept at −80° C. On theday of the experiment, the pellet is resuspended at a concentration of 1g/15 ml and centrifuged at 515 g for 10 minutes at 4° C. The supernatantis used immediately to determine lipidic peroxidation. The homogenate ofrat cerebral cortex (500 μl) is incubated at 37° C. for 15 minutes inthe presence of the compounds to be tested or of the solvent (10 μl).The lipidic peroxidation reaction is initiated by adding 50 μl of FeCl₂at 1 mM, EDTA at 1 mM and ascorbic acid at 4 mM. After incubation for 30minutes at 37° C., the reaction is stopped by adding 50 μl of a solutionof di tertio butyl toluene hydroxyl (BHT, 0.2%). The MDA is quantifiedusing a colorimetric test, by reacting a chromogenic reagent (R),N-methyl-2-phenylindole (650 μl), with 200 μl of the homogenate for 1hour at 45° C. Condensation of a molecule of MDA with two molecules ofreagent R produces a stable chromophore the maximum absorbancewavelength of which is equal to 586 nm. (Caldwell et al. European J.Pharmacol. (1995) 285, 203-206). In this test, the IC₅₀ value of thecompounds according to the invention is lower than 5 μM.

1. Compounds of general formula (I)

in racemic, enantiomeric, diastereoisomeric form or all combinations ofthese forms, in which R¹ represents a hydrogen atom, an —OR³, —SR³, oxoor cyclic acetal radical, in which R³ represents a hydrogen atom, analkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonylor aralkylcarbonyl radical, in which the alkyl, aryl or heterocycloalkylradicals are optionally substituted by one or more identical ordifferent substituents chosen from: alkyl, OH, alkoxy, nitro, cyano,halogen or —NR⁴R⁵; R⁴ and R⁵ represent, independently, a hydrogen atomor an alkyl radical, or R⁴ and R⁵ together with the nitrogen atom towhich they are attached form an optionally substituted heterocycle, R²represents a hydrogen atom, an alkyl, aryl or aralkyl radical, the arylgroup being optionally substituted by one or more identical or differentradicals chosen from: —OR⁶, —NR⁷R⁸, halogen, cyano, nitro or alkyl, inwhich R⁶, R⁷ and R⁸ represent, independently, a hydrogen atom, an alkyl,aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical; Arepresents either an A1 or A′1 radical

in which R⁹, R¹⁰, R¹¹, R¹², R¹³ represent, independently, a hydrogenatom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitro or—NR¹⁵R¹⁶ radical, R¹⁵ and R¹⁶ represent, independently, a hydrogen atom,an alkyl radical or a —COR¹⁷ group, or R¹⁵ and R¹⁶ together with thenitrogen atom to which they are attached form an optionally substitutedheterocycle, R¹⁷ represents a hydrogen atom, an alkyl, alkoxy or—NR¹⁸R¹⁹ radical, R¹⁸ and R¹⁹ represent, independently, a hydrogen atomor an alkyl radical, or R¹⁸ and R¹⁹ together with the nitrogen atom towhich they are attached form an optionally substituted heterocycle, R¹⁴represents a hydrogen atom, an alkyl radical or a —COR²⁰ group, R²⁰represents a hydrogen atom, an alkyl, alkoxy, aryl, aralkyl,heterocycloalkyl or —NR²¹R²² radical, in which the alkyl, aryl orheterocycloalkyl radicals are optionally substituted by one or moreidentical or different substituents chosen from: alkyl, OH, alkoxy,nitro, cyano, halogen or —NR⁴R⁵; R²¹ and R²² represent, independently, ahydrogen atom or an alkyl radical, or R²¹ and R²² together with thenitrogen atom to which they are attached form an optionally substitutedheterocycle, W represents a bond, O or S or also an —NR²³ radical, inwhich R²³ represents a hydrogen atom or an alkyl radical; or an A2radical

in which R²⁴, R²⁵ and R²⁶ represent, independently, a hydrogen, ahalogen, the OH or SR²⁷ group, an alkyl, alkenyl, alkoxy radical or an—NR²⁸R²⁹ radical, R²⁷ represents a hydrogen atom or an alkyl radical,R²⁸ and R²⁹ represent, independently, a hydrogen atom, an alkyl radicalor a —COR³⁰ group, or R²⁸ and R²⁹ form together with the nitrogen atomto which they are attached an optionally substituted heterocycle, R³⁰represents a hydrogen atom, an alkyl, alkoxy or —NR³¹R³² radical, R³¹and R³² represent, independently, a hydrogen atom or an alkyl radical,or R³¹ and R³² together with the nitrogen atom to which they areattached form an optionally substituted heterocycle, Q represents —OR³³,—SR³³, —NR³⁴R³⁵ or an aryl radical substituted by one or more identicalor different substituents chosen from: halogen, the OH group, an alkyl,alkoxy, cyano, nitro or —NR¹⁵R¹⁶ radical, R³³ represents a hydrogenatom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl,arylcarbonyl or aralkylcarbonyl radical, in which the alkyl, aryl orheterocycloalkyl radicals are optionally substituted by one or moreidentical or different substituents chosen from: alkyl, OH, alkoxy,nitro, cyano, halogen or —NR⁴R⁵; R³⁴ and R³⁵ represent, independently, ahydrogen atom, an alkyl radical or a —CO—R³⁶ radical, or together withthe nitrogen atom to which they are attached form an optionallysubstituted heterocycle, R³⁶ representing an alkyl radical; or an A3radical

in which R³⁷ represents a hydrogen atom, an alkyl, arylalkyl,heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonylradical, in which the alkyl, aryl or heterocycloalkyl radicals areoptionally substituted by one or more identical or differentsubstituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or—NR⁴R⁵; T represents a —(CH₂)_(m)— radical with m=1 or 2; or an A4radical

in which R³⁸ represents a hydrogen atom, an alkyl, —(CH₂)_(q)—NR³⁹R⁴⁰ oraralkyl radical, the aryl group being optionally substituted by one ormore identical or different substituents chosen from: OH, alkyl,halogen, nitro, alkoxy or —NR³⁹R⁴⁰, q being an integer comprised between2 and 6; or an A5 radical

in which R′³⁸ and R″³⁸ represent independently a hydrogen atom, nitro,—NR′³⁹R′⁴⁰, an alkyl or arylalkyl radical, the aryl group beingoptionally substituted by one or more identical or differentsubstituents chosen from: OH, the alkyl, halogen, nitro, alkoxy or—NR³⁹R⁴⁰ radicals, R′³⁹, R′⁴⁰, R³⁹ and R⁴⁰ represent, independently, ahydrogen atom, an alkyl radical or a —COR⁴¹ group, or R³⁹ and R⁴⁰ orR′³⁹ and R′⁴⁰ together with the nitrogen atom form an optionallysubstituted heterocycle, R⁴¹ represents a hydrogen atom, an alkyl,alkoxy or —NR⁴²R⁴³ radical, R⁴² and R⁴³ represent, independently, ahydrogen atom or an alkyl radical, or R⁴² and R⁴³ together with thenitrogen atom to which they are attached form an optionally substitutedheterocycle, T representing a —(CH₂)_(m)— radical with m=1 or 2, orfinally an A6 radical

in which R⁴⁴ represents a hydrogen atom, the OH group or an alkyl oralkoxy radical; X represents —(CH₂)_(n)—, —(CH₂)_(n)—CO—,—N(R⁴⁵)—CO—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—D—CO—, —CO—N(R⁴⁵)—CO—, —CO—D—CO—,—CH═CH—(CH₂)_(n)—CO—, —N(R⁴⁵)—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—C(R⁴⁶R⁴⁷)—CO—,—O—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—NH—C(R⁴⁶R⁴⁷)—CO—, —CO—N(R⁴⁵)—C(R⁴⁶R⁴⁷)—CO—,—S—(CH₂)_(n)—CO— or —Z—CO—; D represents a phenylene radical optionallysubstituted by one or more identical or different radicals chosen fromalkyl, alkoxy, OH, nitro, halogen, cyano, or carboxyl optionallyesterified by an alkyl radical; Z represents a heterocycle, R⁴⁵represents a hydrogen atom or an alkyl radical, R⁴⁶ and R⁴⁷ represent,independently, a hydrogen atom, an alkyl, aryl or aralkyl radical thealkyl and aryl groups of which are optionally substituted by one or moreidentical or different substituents chosen from: the OH, —SH, halogen,nitro, alkyl, alkoxy, alkylthio, aralkoxy, aryl-alkylthio, —NR⁴⁸R⁴⁹ andcarboxyl group optionally esterified by an alkyl radical; R⁴⁸ and R⁴⁹represent, independently, a hydrogen atom, an alkyl radical or a —COR⁵⁰group, or R⁴⁸ and R⁴⁹ together with the nitrogen atom to which they areattached form an optionally substituted heterocycle, R⁵⁰ represents ahydrogen atom, an alkyl, alkoxy or —NR⁵¹R⁵² radical, R⁵¹ and R⁵²represent, independently, a hydrogen atom or an alkyl radical, or R⁵¹and R⁵² together with the nitrogen atom to which they are attached, forman optionally substituted heterocycle; n being an integer comprisedbetween 0 and 6; Y represents —(CH₂)_(p)—, —C(R⁵³R⁵⁴)—(CH₂)_(p)—,—C(R⁵³R⁵⁴)—CO—; R⁵³ and R⁵⁴ represent, independently, a hydrogen atom,an alkyl radical, an aralkyl radical the aryl group of which isoptionally substituted by one or more identical or differentsubstituents chosen from: the OH, halogen, nitro, alkyl, alkoxy,—NR⁵⁵R⁵⁶ group, R⁵⁵ and R⁵⁶ represent, independently, a hydrogen atom,an alkyl radical or a —COR⁵⁷ group, or R⁵⁵ and R⁵⁶ together with thenitrogen atom to which they are attached, form an optionally substitutedheterocycle, R⁵⁷ represents a hydrogen atom, an alkyl, alkoxy or—NR⁵⁸R⁵⁹ radical, R⁵⁸ and R⁵⁹ represent, independently, a hydrogen atomor an alkyl radical, or R⁵⁸ and R⁵⁹ together with the nitrogen atom towhich they are attached form an optionally substituted heterocycle; pbeing an integer comprised between 0 and 6; Het represents aheterocycle, as well as the addition salts with mineral and organicacids or with mineral and organic bases of said compounds of generalformula (I), with the exception of the compounds of formula (I) in whichwhen Het represents tetrahydrofuran or tetrahydropyran, R¹ representsthe OR³ radical with R³ representing a hydrogen atom, an alkyl,arylalkyl, heterocycloalkylcarbonyl radical the heterocycloalkyl radicalof which is connected by a carbon atom, alkylcarbonyl, arylcarbonyl oraralkylcarbonyl radical, R² represents a hydrogen and Y represents the—(CH₂)_(p)— radical with p=0, then X does not represent—CO—N(R⁴⁵)—C(R⁴⁶R⁴⁷)—CO— with R⁴⁵═R⁴⁶═H.
 2. Compounds according to claim1, characterized in that Het represents a monocyclic radical containing1 to 2 heteroatoms chosen from O and N.
 3. Compounds according to one ofclaims 1 to 2, characterized in that Het represents tetrahydrofuran,dioxolane, pyrrolidine, 1,3-oxazolidine, and R¹ represents the hydrogenatom, the —OR³ or oxo radical.
 4. Compounds according to one of theprevious claims, characterized in that X represents —(CH₂)_(n)—,—(CH₂)_(n)—CO—, —O—(CH₂)_(n)—CO—, —CO—N(R⁴⁵)—D—CO—,—N(R⁴⁵)—CO—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—C(R⁴⁶R⁴⁷)—CO—,—N(R⁴⁵)—CO—NH—C(R⁴⁶R⁴⁷)—CO—, —N(R⁴⁵)—(CH₂)_(n)—CO—,—CO—N(R⁴⁵)—C(R⁴⁶R⁴⁷)—CO or —Z—CO—.
 5. Compounds according to claim 4,characterized in that R⁴⁵ and R⁴⁷ represent the hydrogen atom, R⁴⁶represents the hydrogen atom, an alkyl or phenyl radical, D representsthe phenylene radical and Z represents the thiazole radical. 6.Compounds according to one of the previous claims, characterized in thatR² represents a hydrogen atom or an aralkyl radical, and preferablybenzyl.
 7. Compounds according to one of the previous claims,characterized in that A represents either A1 with W representing thesulphur atom; or A′1; or A2 with R²⁴, R²⁵ and R²⁶ which represent,independently, a hydrogen or an alkyl radical and Q which represents—OR³³; or A3 with T representing the —(CH₂)₂— radical; or A4 with Trepresenting the —(CH₂)— radical,
 8. Compounds according to one of theprevious claims, characterized in that A represents a radical chosenfrom


9. Compounds corresponding to one of the following formulae:(2R)-6-hydroxy-N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;N-1-(4-anilinophenyl)-N-4-[(3S)-2-hydroxytetrahydro-3-furanyl]succinamide;(3S)-3-{[4-(4-anilinoanilino)-4-oxobutanoyl]amino}tetrahydro-2-furanylacetate;N-1-(4-anilinophenyl)-N-4-[(1S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl]succinamide;N-1-(4-anilinophenyl)-N-3-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenylmalonamide;3-(4-anilinoanilino)tetrahydro-2-furanol;N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)-amino]pentanoyl}amino)tetrahydro-2-furanylacetate;N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;N-[4-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylpivalate;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl3,3-dimethylbutanoate;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylbenzoate;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylphenylacetate;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl(2S)-2-(dimethylamino)-3-phenylpropanoate;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl4-morpholinecarboxylate;N-{(1S)-3-methyl-1-[(3-oxo-1-pyrrolidinyl)carbonyl]butyl}-10H-phenothiazine-2-carboxamide;2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-hydroxytetrahydro-3-furanyl]acetamide;N¹-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenyl-N³-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide;N-(2-anilinophenyl)-N′-[(3S)-2-hydroxytetrahydro-3-furanyl]urea;N¹-[(3S)-2-hydroxytetrahydro-3-furanyl]-N²-(1-propyl-2,3-dihydro-1H-indol-5-yl)ethanediamide;(2R)-N-[(1S)-1-(1,3-dioxolan-2-yl)-2-phenylethyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;N-[(3S)-2-hydroxytetrahydro-3-furanyl]-5-indolinecarboxamide.
 10. Asmedicaments, compounds according to one of claims 1 to
 9. 11.Pharmaceutical compositions comprising, as active ingredient, at leastone medicament as defined in claim
 10. 12. Use of compounds of formula(I_(a)) as defined above,

in racemic, enantiomeric, diastereoisomeric form or all combinations ofthese forms, in which R_(a) ¹ represents a hydrogen atom, an —OR³, —SR³,oxo or cyclic acetal radical, in which R³ represents a hydrogen atom, analkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonylor aralkylcarbonyl radical, in which the alkyl, aryl or heterocycloalkylradicals are optionally substituted by one or more identical ordifferent substituents chosen from: alkyl, OH, alkoxy, nitro, cyano,halogen or —NR⁴R⁵; R⁴ and R⁵ represent, independently, a hydrogen atomor an alkyl radical, or R⁴ and R⁵ together with the nitrogen atom towhich they are attached form an optionally substituted heterocycle,R_(a) ² represents a hydrogen atom, an alkyl, aryl or aralkyl radical,the aryl group being optionally substituted by one or more identical ordifferent radicals chosen from: —OR⁶, —NR⁷R⁸, halogen, cyano, nitro oralkyl, in which R⁶, R⁷ and R⁸ represent, independently, a hydrogen atom,an alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonylradical; A_(a) represents either an A1 or A′1 radical

in which R⁹, R¹⁰, R¹¹, R¹², R¹³ represent, independently, a hydrogenatom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitro or—NR¹⁵R¹⁶ radical, R¹⁵ and R¹⁶ represent, independently, a hydrogen atom,an alkyl radical or a —COR¹⁷ group, or R¹⁵ and R¹⁶ together with thenitrogen atom to which they are attached form an optionally substitutedheterocycle, R¹⁷ represents a hydrogen atom, an alkyl, alkoxy or—NR¹⁸R¹⁹ radical, R¹⁸ and R¹⁹ represent, independently, a hydrogen atomor an alkyl radical, or R¹⁸ and R¹⁹ together with the nitrogen atom towhich they are attached form an optionally substituted heterocycle, R¹⁴represents a hydrogen atom, an alkyl radical or a —COR²⁰ group, R²⁰represents a hydrogen atom, an alkyl, alkoxy, aryl, aralkyl,heterocycloalkyl or —NR²¹ R²² radical, in which the alkyl, aryl orheterocycloalkyl radicals are optionally substituted by one or moreidentical or different substituents chosen from: alkyl, OH, alkoxy,nitro, cyano, halogen or —NR⁴R⁵; R²¹ and R²² represent, independently, ahydrogen atom or an alkyl radical, or R²¹ and R²² together with thenitrogen atom to which they are attached form an optionally substitutedheterocycle, W represents a bond, O or S or also an —NR²³ radical, inwhich R²³ represents a hydrogen atom or an alkyl radical; or an A2radical

in which R²⁴, R²⁵ and R²⁶ represent, independently, a hydrogen, ahalogen, the OH or SR²⁷ group, an alkyl, alkenyl, alkoxy radical or an—NR²⁸R²⁹ radical, R²⁷ represents a hydrogen atom or an alkyl radical,R²⁸ and R²⁹ represent, independently, a hydrogen atom, an alkyl radicalor a —COR³⁰ group, or R²⁸ and R²⁹ together with the nitrogen atom towhich they are attached form an optionally substituted heterocycle, R³⁰represents a hydrogen atom, an alkyl, alkoxy or —NR³¹R³² radical, R³¹and R³² represent, independently, a hydrogen atom or an alkyl radical,or R³¹ and R³² together with the nitrogen atom to which they areattached form an optionally substituted heterocycle, Q represents —OR³³,—SR³³, —NR³⁴R³⁵ or an aryl radical substituted by one or more identicalor different substituents chosen from: halogen, the OH group, an alkyl,alkoxy, cyano, nitro or —NR¹⁵R¹⁶ radical, R³³ represents a hydrogenatom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl,arylcarbonyl or aralkylcarbonyl radical, in which the alkyl, aryl orheterocycloalkyl radicals are optionally substituted by one or moreidentical or different substituents chosen from: alkyl, OH, alkoxy,nitro, cyano, halogen or —NR⁴R⁵; R³⁴ and R³⁵ represent, independently, ahydrogen atom, an alkyl radical or a —CO—R³⁶ radical, or together withthe nitrogen atom to which they are attached form an optionallysubstituted heterocycle, R³⁶ representing an alkyl radical; or an A3radical

in which R³⁷ represents a hydrogen atom, an alkyl, arylalkyl,heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonylradical, in which the alkyl, aryl or heterocycloalkyl radicals areoptionally substituted by one or more identical or differentsubstituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or—NR⁴R⁵; T represents a —(CH₂)_(m)— radical with m=1 or 2; or an A4radical

in which R³⁸ represents a hydrogen atom, an alkyl, —(CH₂)_(q)—NR³⁹R⁴⁰ oraralkyl radical, the aryl group being optionally substituted by one ormore identical or different substituents chosen from: OH, alkyl,halogen, nitro, alkoxy or —NR³⁹R⁴⁰, q being an integer comprised between2 and 6; or an A5 radical

in which R′³⁸ and R″³⁸ represent independently a hydrogen atom, nitro,—NR′³⁹R′⁴⁰, an alkyl or arylalkyl radical, the aryl group beingoptionally substituted by one or more identical or differentsubstituents chosen from: OH, the alkyl, halogen, nitro, alkoxy or—NR³⁹R⁴⁰ radicals, R′³⁹, R′⁴⁰, R³⁹ and R⁴⁰ represent, independently, ahydrogen atom, an alkyl radical or a —COR⁴¹ group, or R³⁹ and R⁴⁰ orR′³⁹ and R′⁴⁰ together with the nitrogen atom form an optionallysubstituted heterocycle, R⁴¹ represents a hydrogen atom, an alkyl,alkoxy or —NR⁴²R⁴³ radical, R⁴² and R⁴³ represent, independently, ahydrogen atom or an alkyl radical, or R⁴² and R⁴³ together with thenitrogen atom to which they are attached form an optionally substitutedheterocycle, T representing a —(CH₂)_(m)— radical with m=1 or 2, orfinally an A6 radical

in which R⁴⁴ represents a hydrogen atom, the OH group or an alkyl oralkoxy radical; X_(a) represents —(CH₂)_(n)—, —(CH₂)_(n)—CO—,—N(R⁴⁵)—CO—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—D—CO—, —CO—N(R⁴⁵)—D—CO—, —CO—D—CO—,—CH═CH—(CH₂)_(n)—CO—, —N(R⁴⁵)—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—C(R⁴⁶R⁴⁷)—CO—,—O—(CH₂)_(n)—CO—, —N(R⁴⁵)—CO—NH—C(R⁴⁶R⁴⁷)—CO—, —CO—N(R⁴⁵)—C(R⁴⁶R⁴⁷)—CO—,—S—(CH₂)_(n)—CO— or —Z—C O—; D represents a phenylene radical optionallysubstituted by one or more identical or different radicals chosen fromalkyl, alkoxy, OH, nitro, halogen, cyano, or carboxyl optionallyesterified by an alkyl radical; Z represents a heterocycle, R⁴⁵represents a hydrogen atom or an alkyl radical, R⁴⁶ and R⁴⁷ represent,independently, a hydrogen atom, an alkyl, aryl or aralkyl radical thealkyl and aryl groups of which are optionally substituted by one or moreidentical or different substituents chosen from: the OH, —SH, halogen,nitro, alkyl, alkoxy, alkylthio, aralkoxy, aryl-alkylthio, —NR⁴⁸R⁴⁹ andcarboxyl group optionally esterified by an alkyl radical; R⁴⁸ and R⁴⁹represent, independently, a hydrogen atom, an alkyl radical or a —COR⁵⁰group, or R⁴⁸ and R⁴⁹ together with the nitrogen atom to which they areattached form an optionally substituted heterocycle, R⁵⁰ represents ahydrogen atom, an alkyl, alkoxy or —NR⁵¹R⁵² radical, R⁵¹ and R⁵²represent, independently, a hydrogen atom or an alkyl radical, or R⁵¹and R⁵² together with the nitrogen atom to which they are attached forman optionally substituted heterocycle; n being an integer comprisedbetween 0 and 6; Y_(a) represents —(CH₂)_(p)—, —C(R⁵³R⁵⁴)—(CH₂)_(p)—,—C(R⁵³R⁵⁴)—CO—; R⁵³ and R⁵⁴ represent, independently, a hydrogen atom,an alkyl radical, an aralkyl radical the aryl group of which isoptionally substituted by one or more identical or differentsubstituents chosen from: the OH group, halogen, nitro, alkyl, alkoxy,—NR⁵⁵R⁵⁶, R⁵⁵ and R⁵⁶ represent, independently, a hydrogen atom, analkyl radical or a —COR⁵⁷ group, or R⁵⁵ and R⁵⁶ together with thenitrogen atom to which they are attached form an optionally substitutedheterocycle, R⁵⁷ represents a hydrogen atom, an alkyl, alkoxy or—NR⁵⁸R⁵⁹ radical, R⁵⁸ and R⁵⁹ represent, independently, a hydrogen atomor an alkyl radical, or R⁵⁸ and R⁵⁹ together with the nitrogen atom towhich they are attached form an optionally substituted heterocycle; pbeing an integer comprised between 0 and 6; Het_(a) represents aheterocycle, as well as addition salts with mineral and organic acids orwith mineral and organic bases of said compounds of general formula (I),for the preparation of medicaments for the treatment of pathologieswhere calpains and/or reactive oxygen species are involved.
 13. Use ofcompounds of formula (I_(a)) according to claim 12, for the preparationof medicaments for the treatment of pathologies involving reactiveoxygen species.
 14. Use of compounds of formula (I_(a)) according toclaim 12, for the preparation of medicaments for the treatment ofpathologies involving reactive oxygen species and calpains.
 15. Use ofcompounds of formula (I_(a)) according to one of claims 12 to 14, forthe preparation of medicaments for the treatment of pathologies ofinflammatory and immunological diseases, cardiovascular andcerebrovascular diseases, disorders of the central or peripheral nervoussystem, osteoporosis, muscular dystrophies, proliferative diseases,cataracts, organ transplants, auto-immune and viral diseases, cancer,and all pathologies characterized by the excessive production of ROS'sand/or activation of calpains.
 16. Use of compounds of formula (I_(a))according to one of claims 12 to 15, characterized in that Hetrepresents a monocyclic radical containing 1 to 2 heteroatoms chosenfrom O and N.
 17. Use of compounds of formula (I_(a)) according to oneof claims 12 to 16, characterized in that Het representstetrahydrofuran, dioxolane, pyrrolidine, 1,3-oxazolidine, and R¹represents the hydrogen atom, the —OR³ or oxo radical.
 18. Use ofcompounds of formula (I_(a)) according to one of claims 12 to 17,characterized in that X represents —(CH₂)_(n)—, —(CH₂)_(n)—CO—,—O—(CH₂)_(n)—CO—, —CO—N(R⁴⁵)—D—CO—, —N(R⁴⁵)—CO—(CH₂)_(n)—CO—,—N(R⁴⁵)—CO—C(R⁴⁶R⁴⁷)—CO—, —N(R⁴⁵)—CO—NH—C(R⁴⁶R⁴⁷)—CO—,—N(R⁴⁵)—(CH₂)_(n)—CO—, —CO—N(R⁴⁵)—C(R⁴⁶R⁴⁷)—CO or —Z—CO—.
 19. Use ofcompounds of formula (I_(a)) according to claim 18, characterized inthat R⁴⁵ and R⁴⁷ represent the hydrogen atom, R⁴⁶ represents thehydrogen atom, an alkyl or phenyl radical, D represents the phenyleneradical and Z represents the thiazole radical.
 20. Use of compounds offormula (I_(a)) according to one of claims 12 to 19, characterized inthat R² represents a hydrogen atom or an aralkyl radical, and preferablybenzyl.
 21. Use of compounds of formula (I_(a)) according to one ofclaims 12 to 20, characterized in that A represents either A1 with Wrepresenting the sulphur atom; or A′1; or A2 with R²⁴, R²⁵ and R²⁶ whichrepresent, independently, a hydrogen or an alkyl radical and Q whichrepresents —OR³³; or A3 with T representing the —(CH₂)₂— radical; or A4with T representing the —(CH₂)— radical,
 22. Use of compounds of formula(I_(a)) according to one of claims 12 to 21, characterized in that Arepresents a radical chosen from


23. Use of compounds of formula (I_(a)) according to one of claims 12 to22, characterized in that they correspond to one of the followingformulae:(2R)-6-hydroxy-N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;N-1-(4-anilinophenyl)-N-4-[(3S)-2-hydroxytetrahydro-3-furanyl]succinamide;(3S)-3-{[4-(4-anilinoanilino)-4-oxobutanoyl]amino}tetrahydro-2-furanylacetate;N-1-(4-anilinophenyl)-N-4-[(1S)-1-(1,3-dioxolan-2-yl)-3-methylbutyl]succinamide;N-1-(4-anilinophenyl)-N-3-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenylmalonamide;3-(4-anilinoanilino)tetrahydro-2-furanol;N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)-amino]pentanoyl}amino)tetrahydro-2-furanylacetate;N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;N-[4-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylpivalate;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl3,3-dimethylbutanoate;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylbenzoate;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanylphenylacetate;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl(2S)-2-(dimethylamino)-3-phenylpropanoate;(3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl4-morpholinecarboxylate;N-{(1S)-3-methyl-1-[(3-oxo-1-pyrrolidinyl)carbonyl]butyl}-10H-phenothiazine-2-carboxamide;2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-hydroxytetrahydro-3-furanyl]acetamide;N¹-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-phenyl-N³-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide;N-(2-anilinophenyl)-N′-[(3S)-2-hydroxytetrahydro-3-furanyl]urea;N¹-[(3S)-2-hydroxytetrahydro-3-furanyl]-N²-(1-propyl-2,3-dihydro-1H-indol-5-yl)ethanediamide;(2R)-N-[(1S)-1-(1,3-dioxolan-2-yl)-2-phenylethyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;N-[(3S)-2-hydroxytetrahydro-3-furanyl]-5-indolinecarboxamide.
 24. Asindustrial products, the compounds corresponding to one of the followingformulae:N-1-(4-anilinophenyl)-N-4-[(3S)-2-oxotetrahydro-3-furanyl]succinamide;methyl(2S)-2-{[4-(4-anilinoanilino)-4-oxobutanoyl]amino}-4-methylpentanoate;N-1-(4-anilinophenyl)-N4-[(1S)-1-formyl-3-methylbutyl]succinamide;benzyl 3-(4-anilinoanilino)-3-oxo-2-phenylpropanoate;3-(4-anilinoanilino)-3-oxo-2-phenylpropanoic acid;N-1-(4-anilinophenyl)-N-3-[(3S)-2-oxotetrahydro-3-furanyl]-2-phenylmalonamide;3-(4-anilinoanilino)dihydro-2(3H)-furanone; methyl(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoate;(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoic acid;N-[(1S)-3-methyl-1-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)butyl]-10H-phenothiazine-2-carboxamide;ethyl 2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxylate;2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxylic acid;N-[(3S)-2-oxotetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;methyl 4-[(10H-phenothiazin-2-ylcarbonyl)amino]benzoate;4-[(10H-phenothiazin-2-ylcarbonyl)amino]benzoic acid;N-[4-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;methyl (2S)-4-methyl-2-[(10H-phenothiazin-1-ylcarbonyl)amino]pentanoate;(2S)-4-methyl-2-[(10H-phenothiazin-1-ylcarbonyl)amino]pentanoic acid;N-[(1S)-1-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;N-[(1S)-1-(1,4-dioxa-7-azaspiro[4.4]non-7-ylcarbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;2-(3,5-di-tert-butyl-4-hydroxyphenoxy)-N-[(3S)-2-oxotetrahydro-3-furanyl]acetamide5-nitro-1-propylindoline; 1-propyl-2,3-dihydro-1H-indol-5-ylamine;3-oxo-2-phenyl-N-(1-propyl-2,3-dihydro-1H-indol-5-yl)-beta-alanine;N¹-[(3S)-2-oxotetrahydro-3-furanyl]-2-phenyl-N³-(1-propyl-2,3-dihydro-1H-indol-5-yl)malonamide;N-(2-anilinophenyl)-N′-[(3S)-2-oxotetrahydro-3-furanyl]urea; ethyloxo[(1-propyl-2,3-dihydro-1H-indol-5-yl)amino]acetate;oxo[(1-propyl-2,3-dihydro-1H-indol-5-yl)amino]acetic acid; methyl(2S)-2-({[(2R)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl]carbonyl}amino)-3-phenylpropanoate;(2R)-N-[(1S)-1-benzyl-2-oxoethyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxamide;tert-butyl 5-methyl 1,5-indolinedicarboxylate;1-(tert-butoxycarbonyl)-5-indolinecarboxylic acid; tert-butyl5-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)-1-indolinecarboxylate; tert-butyl5-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-1-indolinecarboxylate.